U.S. patent application number 13/830907 was filed with the patent office on 2014-01-16 for methods of inducing anesthesia.
The applicant listed for this patent is The Regents of the University of California. Invention is credited to Robert J. Brosnan.
Application Number | 20140018414 13/830907 |
Document ID | / |
Family ID | 49914505 |
Filed Date | 2014-01-16 |
United States Patent
Application |
20140018414 |
Kind Code |
A1 |
Brosnan; Robert J. |
January 16, 2014 |
METHODS OF INDUCING ANESTHESIA
Abstract
The present invention provides methods for determining the
selectivity of an anesthetic for an anesthetic-sensitive receptor
by determining the molar water solubility of the anesthetic. The
invention further provides methods for modulating the selectivity
of an anesthetic for an anesthetic-sensitive receptor by altering
or modifying the anesthetic to have higher or lower water
solubility. The invention further provides methods of inducing
anesthesia in a subject by administering via the respiratory
pathways (e.g., via inhalational or pulmonary delivery) an
effective amount of an anesthetic compound identified according to
the present methods.
Inventors: |
Brosnan; Robert J.; (Davis,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Regents of the University of California |
Oakland |
CA |
US |
|
|
Family ID: |
49914505 |
Appl. No.: |
13/830907 |
Filed: |
March 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61681747 |
Aug 10, 2012 |
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61670098 |
Jul 10, 2012 |
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Current U.S.
Class: |
514/452 ;
514/451; 514/461; 514/467; 514/724; 514/747; 549/380; 549/428;
549/455; 549/504; 568/841; 570/124; 570/131; 73/61.41 |
Current CPC
Class: |
A61M 16/01 20130101;
A61P 43/00 20180101; A61P 23/00 20180101; A61D 7/04 20130101; A61K
9/007 20130101; A61K 31/025 20130101; A61K 31/351 20130101; A61K
31/357 20130101; A61K 31/02 20130101; A61P 25/20 20180101; A61P
11/00 20180101; A61K 31/08 20130101; A61K 31/341 20130101; A61K
31/045 20130101 |
Class at
Publication: |
514/452 ;
570/124; 514/747; 549/428; 514/451; 549/504; 514/461; 570/131;
549/455; 514/467; 568/841; 514/724; 549/380; 73/61.41 |
International
Class: |
A61K 31/357 20060101
A61K031/357; A61K 31/045 20060101 A61K031/045; A61K 31/341 20060101
A61K031/341; A61K 31/025 20060101 A61K031/025; A61K 31/351 20060101
A61K031/351 |
Goverment Interests
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] This invention was made with government support under Grant
No. GM092821 awarded by National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
V: ##STR00017## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X and C.sub.2X.sub.5; and wherein X is a halogen, the
compound has a vapor pressure of at least 0.1 atmospheres (76 mmHg)
at 25.degree. C., and the number of hydrogen atoms of Formula V do
not exceed the number of carbon atoms, thereby inducing anesthesia
in the subject.
2. The method of claim 1, wherein X is a halogen selected from the
group consisting of F, Cl, Br and I.
3. The method of claim 1, wherein X is F or Cl.
4. The method of claim 1, wherein the compound is selected from the
group consisting of: a) Cyclopentane,
5-chloro-1,1,2,2,3,3,4,4-octafluoro-(CAS#362014-70-8); b)
Cyclopentane, 1,1,2,2,3,4,4,5-octafluoro-(CAS#773-17-1); c)
Cyclopentane, 1,1,2,2,3,3,4,5-octafluoro-(CAS#828-35-3); d)
Cyclopentane, 1,1,2,3,3,4,5-heptafluoro-(CAS#3002-03-7); e)
Cyclopentane, 1,1,2,2,3,3,4,4-octafluoro-(CAS#149600-73-7); f)
Cyclopentane, 1,1,2,2,3,4,5-heptafluoro-(CAS#1765-23-7); g)
Cyclopentane, 1,1,2,3,4,5-hexafluoro-(CAS#699-38-7); h)
Cyclopentane, 1,1,2,2,3,3,4-heptafluoro-(CAS#15290-77-4); i)
Cyclopentane, 1,1,2,2,3,4-hexafluoro-(CAS#199989-36-1); j)
Cyclopentane, 1,1,2,2,3,3-hexafluoro-(CAS#123768-18-3); and k)
Cyclopentane, 1,1,2,2,3-pentafluoro-(CAS#1259529-57-1).
5. The method of claim 1, wherein the compound is selected from the
group consisting of: c) Cyclopentane,
1,1,2,2,3,3,4,5-octafluoro-(CAS#828-35-3); e) Cyclopentane,
1,1,2,2,3,3,4,4-octafluoro-(CAS#149600-73-7); and h) Cyclopentane,
1,1,2,2,3,3,4-heptafluoro-(CAS#15290-77-4).
6. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
I: ##STR00018## wherein: n is 0-4, R.sup.1 is H; R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 independently are selected from H, X,
CX.sub.3, CHX.sub.2, CH.sub.2X and C.sub.2X.sub.5; and wherein X is
a halogen, the compound having vapor pressure of at least 0.1
atmospheres (76 mmHg) at 25.degree. C., and the number of hydrogen
atoms in Formula I do not exceed the number of carbon atoms,
thereby inducing anesthesia in the subject.
7. The method of claim 6, wherein X is a halogen selected from the
group consisting of F, Cl, Br and I.
8. The method of claim 6, wherein X is F or Cl.
9. The method of claim 6, wherein the compound is selected from the
group consisting of: a) Methanol,
1-fluoro-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]-(CAS
#1351959-82-4); b) 1-Butanol,
4,4,4-trifluoro-3,3-bis(trifluoromethyl)-(CAS#14115-49-2); c)
1-Butanol, 1,1,2,2,3,3,4,4,4-nonafluoro-(CAS#3056-01-7); d)
1-Butanol,
2,2,3,4,4,4-hexafluoro-3-(trifluoromethyl)-(CAS#782390-93-6); e)
1-Butanol,
3,4,4,4-tetrafluoro-3-(trifluoromethyl)-(CAS#90999-87-4); f)
1-Pentanol, 1,1,4,4,5,5,5-heptafluoro-(CAS#313503-66-1); and g)
1-Pentanol,
1,1,2,2,3,3,4,4,5,5,5-undecafluoro-(CAS#57911-98-5).
10. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
II: ##STR00019## wherein: n is 1-3, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are
selected from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and
C.sub.2X.sub.5; and wherein X is a halogen, the compound having
vapor pressure of at least 0.1 atmospheres (76 mmHg) at 25.degree.
C., and the number of hydrogen atoms in Formula II do not exceed
the number of carbon atoms, thereby inducing anesthesia in the
subject.
11. The method of claim 10, wherein X is a halogen selected from
the group consisting of F, Cl, Br and I.
12. The method of claim 10, wherein X is F or Cl.
13. The method of claim 10, wherein the compound is selected from
the group consisting of: a) Ethane,
1,1,2-trifluoro-1,2-bis(trifluoromethoxy)-(CAS#362631-92-3); b)
Ethane,
1,1,1,2-tetrafluoro-2,2-bis(trifluoromethoxy)-(CAS#115395-39-6); c)
Ethane,
1-(difluoromethoxy)-1,1,2,2-tetrafluoro-2-(trifluoromethoxy)-(CAS-
#40891-98-3); d) Ethane,
1,1,2,2-tetrafluoro-1,2-bis(trifluoromethoxy)-(CAS#378-11-0); e)
Ethane, 1,2-difluoro-1,2-bis(trifluoromethoxy)-(CAS#362631-95-6);
f) Ethane, 1,2-bis(trifluoromethoxy)-(CAS#1683-90-5); g) Propane,
1,1,3,3-tetrafluoro-1,3-bis(trifluoromethoxy)-(CAS#870715-97-2); h)
Propane, 2,2-difluoro-1,3-bis(trifluoromethoxy)-(CAS#156833-18-0);
i) Propane,
1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethoxy)-(CAS#133640-
-19-4; j) Propane,
1,1,1,3,3,3-hexafluoro-2-(fluoromethoxymethoxy)-(CAS#124992-92-3);
and k) Propane,
1,1,1,2,3,3-hexafluoro-3-methoxy-2-(trifluoromethoxy)-(CAS#10415-
9-55-9).
14. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
III: ##STR00020## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are selected
from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and C.sub.2X.sub.5; and
wherein X is a halogen, the compound has a vapor pressure of at
least 0.1 atmospheres (76 mmHg) at 25.degree. C., and the number of
hydrogen atoms of Formula III do not exceed the number of carbon
atoms, thereby inducing anesthesia in the subject.
15. The method of claim 14, wherein X is a halogen selected from
the group consisting of F, Cl, Br and I.
16. The method of claim 14, wherein X is F or Cl.
17. The method of claim 14, wherein the compound is selected from
the group consisting of a) 1,4-Dioxane,
2,2,3,3,5,6-hexafluoro-(CAS#362631-99-0); b) 1,4-Dioxane,
2,3-dichloro-2,3,5,5,6,6-hexafluoro-(CAS#135871-00-0); c)
1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-, trans-(9CI)
(CAS#56625-45-7); d) 1,4-Dioxane,
2,3-dichloro-2,3,5,5,6,6-hexafluoro-, cis-(9CI) (CAS#56625-44-6);
e) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro-(CAS#56269-26-2); f)
1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-(CAS#56269-25-1); g)
1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, trans-(9CI) (CAS#34206-83-2);
h) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-, cis-(9CI)
(CAS#34181-52-7); i) p-Dioxane, 2,2,3,5,5,6-hexafluoro-,
trans-(8CI) (CAS#34181-51-6); j) 1,4-Dioxane,
2,2,3,5,6,6-hexafluoro-, cis-(9CI) (CAS#34181-50-5); k) p-Dioxane,
2,2,3,5,6,6-hexafluoro-, trans-(8C1) (CAS#34181-49-2); l)
1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, (5R,6S)-rel-(CAS#34181-48-1);
m) 1,4-Dioxane, 2,2,3,3,5,5,6-heptafluoro-(CAS#34118-18-8); and n)
1,4-Dioxane, 2,2,3,3,5,5,6,6-octafluoro-(CAS#32981-22-9).
18. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
IV: ##STR00021## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 independently are selected from H, X, CX.sub.3,
CHX.sub.2, CH.sub.2X and C.sub.2X.sub.5; and wherein X is a
halogen, the compound has a vapor pressure of at least 0.1
atmospheres (76 mmHg) at 25.degree. C., and the number of hydrogen
atoms of Formula IV do not exceed the number of carbon atoms,
thereby inducing anesthesia in the subject.
19. The method of claim 18, wherein X is a halogen selected from
the group consisting of F, Cl, Br and I.
20. The method of claim 18, wherein X is F or Cl.
21. The method of claim 18, wherein the compound is selected from
the group consisting of: a) 1,3-Dioxolane,
2,4,4,5-tetrafluoro-5-(trifluoromethyl)-(CAS#344303-08-8); b)
1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-(CAS#344303-05-5); c)
1,3-Dioxolane,
4,4,5,5-tetrafluoro-2-(trifluoromethyl)-(CAS#269716-57-6); d)
1,3-Dioxolane,
4-chloro-2,2,4-trifluoro-5-(trifluoromethyl)-(CAS#238754-29-5); e)
1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-, trans-(9CI) (CAS
#162970-78-7); f) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-,
cis-(9CI) (CAS#162970-76-5); g) 1,3-Dioxolane,
4-chloro-2,2,4,5,5-pentafluoro-(CAS#139139-68-7); h) 1,3-Dioxolane,
4,5-dichloro-2,2,4,5-tetrafluoro-(CAS#87075-00-1); i)
1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-,
trans-(9CI) (CAS#85036-66-4); j) 1,3-Dioxolane,
2,4,4,5-tetrafluoro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#85036-65-3); k) 1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-, trans-(9CI)
(CAS#85036-60-8); l) 1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#85036-57-3); m) 1,3-Dioxolane,
2,2-dichloro-4,4,5,5-tetrafluoro-(CAS#85036-55-1); n)
1,3-Dioxolane,
4,4,5-trifluoro-5-(trifluoromethyl)-(CAS#76492-99-4); o)
1,3-Dioxolane,
4,4-difluoro-2,2-bis(trifluoromethyl)-(CAS#64499-86-1); p)
1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-, cis-(9CI)
(CAS#64499-85-0); q) 1,3-Dioxolane,
4,5-difluoro-2,2-bis(trifluoromethyl)-, trans-(9CI)
(CAS#64499-66-7); r) 1,3-Dioxolane,
4,4,5-trifluoro-2,2-bis(trifluoromethyl)-(CAS#64499-65-6); s)
1,3-Dioxolane,
2,4,4,5,5-pentafluoro-2-(trifluoromethyl)-(CAS#55135-01-8); t)
1,3-Dioxolane, 2,2,4,4,5,5-hexafluoro-(CAS#21297-65-4); and u)
1,3-Dioxolane,
2,2,4,4,5-pentafluoro-5-(trifluoromethyl)-(CAS#19701-22-5).
22. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of 1,1,2,2,3,3,4,4-octafluoro-cyclohexane
(CAS#830-15-9), thereby inducing anesthesia in the subject.
23. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
VI: ##STR00022## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are selected
from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and C.sub.2X.sub.5; and
wherein X is a halogen, the compound has a vapor pressure of at
least 0.1 atmospheres (76 mmHg) at 25.degree. C., and the number of
hydrogen atoms of Formula VI do not exceed the number of carbon
atoms, thereby inducing anesthesia in the subject.
24. The method of claim 23, wherein X is a halogen selected from
the group consisting of F, Cl, Br and I.
25. The method of claim 23, wherein X is F or Cl.
26. The method of claim 23, wherein the compound is selected from
the group consisting of: a) Furan,
2,3,4,4-tetrafluorotetrahydro-2,3-bis(trifluoromethyl)-(CAS#634191-25-6);
b) Furan,
2,2,3,3,4,4,5-heptafluorotetrahydro-5-(trifluoromethyl)-(CAS#37-
7-83-3); c) Furan,
2,2,3,3,4,5,5-heptafluorotetrahydro-4-(trifluoromethyl)-(CAS#374-53-8);
d) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2a,3.beta.,4a)-(9CI) (CAS#133618-53-8); e) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2a,3a,4B)-(CAS#133618-52-7); f) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2.alpha.,3.beta.,4.alpha.)-(9CI) (CAS#133618-53-8); g) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2.alpha.,3.alpha.,4.beta.)-(9CI) (CAS#133618-52-7); h) Furan,
2,2,3,3,5,5-hexafluorotetrahydro-4-(trifluoromethyl)-(CAS#61340-70-3);
i) Furan,
2,3-difluorotetrahydro-2,3-bis(trifluoromethyl)-(CAS#634191-26-7);
j) Furan,
2-chloro-2,3,3,4,4,5,5-heptafluorotetrahydro-(CAS#1026470-51-8)- ;
k) Furan,
2,2,3,3,4,4,5-heptafluorotetrahydro-5-methyl-(CAS#179017-83-5); l)
Furan, 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-,
trans-(9CI) (CAS#133618-59-4); and m) Furan,
2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#133618-49-2).
27. A method of inducing anesthesia in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
VII: ##STR00023## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X, and C.sub.2X.sub.5; and wherein X is a halogen, the
compound has a vapor pressure of at least 0.1 atmospheres (76 mmHg)
at 25.degree. C., and the number of hydrogen atoms of Formula VII
do not exceed the number of carbon atoms, thereby inducing
anesthesia in the subject.
28. The method of claim 27, wherein X is a halogen selected from
the group consisting of F, Cl, Br and I.
29. The method of claim 27, wherein X is F or Cl.
30. The method of claim 27, wherein the compound is selected from
the group consisting of: a) 2H-Pyran,
2,2,3,3,4,5,5,6,6-nonafluorotetrahydro-4-(CAS #71546-79-7); b)
2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-(trifluoromethyl)-(CAS#356-47-8)-
; c) 2H-Pyran,
2,2,3,3,4,4,5,6,6-nonafluorotetrahydro-5-(trifluoromethyl)-(CAS#61340-74--
7); d) 2H-Pyran,
2,2,6,6-tetrafluorotetrahydro-4-(trifluoromethyl)-(CAS#657-48-7);
e) 2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-methyl-(CAS#874634-55--
6); f) Perfluorotetrahydropyran (CAS#355-79-3); g) 2H-Pyran,
2,2,3,3,4,5,5,6-octafluorotetrahydro-,
(4R,6S)-rel-(CAS#362631-93-4); and h) 2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-(CAS#65601-69-6).
31. The method of claim 6, wherein the compound has a molar water
solubility of less than about 1.1 mM and greater than about 0.016
mM.
32. The method of claim 6, wherein the compound potentiates
GABA.sub.A receptors, but does not inhibit NMDA receptors.
33. The method of claim 6, wherein the subject is a mammal.
34. The method of claim 6, wherein the subject is a human.
35. A composition comprising a compound or a mixture of compounds
used in the methods of claim 6, wherein the composition is
formulated for inhalational or pulmonary delivery of the compound
or mixture of compounds.
36. A method of selecting an anesthetic that preferentially
activates or potentiates GABA.sub.A receptors without inhibiting
NMDA receptors, comprising: a) determining the molar water
solubility of the anesthetic; and b) selecting an anesthetic with a
molar water solubility below about 1.1 mM, wherein the anesthetic
selectively potentiates GABA.sub.A receptors and does not inhibit
NMDA receptors, whereby an anesthetic that preferentially activates
or potentiates GABA.sub.A receptors without inhibiting NMDA
receptors is selected.
37. A method of selecting an anesthetic that both potentiates
GABA.sub.A receptors and inhibits NMDA receptors, comprising: a)
determining the molar water solubility of the anesthetic; and b)
selecting an anesthetic with a molar water solubility above about
1.1 mM, wherein the anesthetic both potentiates GABA.sub.A
receptors and inhibits NMDA receptors, whereby an anesthetic that
both potentiates GABA.sub.A receptors and inhibits NMDA receptors
is selected.
38. The method of claim 36, wherein the anesthetic is an
inhalational anesthetic.
39. The method of claim 36, wherein the anesthetic is selected from
the group consisting of halogenated alcohols, halogenated diethers,
halogenated dioxanes, halogenated dioxolanes, halogenated
cyclopentanes, halogenated cyclohexanes, halogenated
tetrahydrofurans and halogenated tetrahydropyrans, wherein the
anesthetic has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms do not
exceed the number of carbon atoms.
40. The method of claim 36, wherein the anesthetic is selected from
the compounds administered in the methods of any one of claims 6 to
32.
41. The method of claim 36, wherein the anesthetic is selected from
the group consisting of nonane, midazolam, diazepam, undecanol,
etomidate, 1,2-dichlorohexafluorocyclobutane, and analogs
thereof.
42. The method of claim 37, wherein the anesthetic is selected from
the group consisting of sevoflurane, propofol, ketamine,
isoflurane, enflurane, dizocilpine, desflurane, halothane,
cyclopropane, chloroform, 2,6-dimethylphenol, methoxyflurane,
diethyl ether, nitrous oxide, ethanol, and analogs thereof.
43. A method of determining the specificity of an anesthetic for an
anesthetic-sensitive receptor comprising determining whether the
molar water solubility of the anesthetic is above or below a
predetermined solubility threshold concentration for an
anesthetic-sensitive receptor, wherein an anesthetic with a molar
water solubility below about 1.2 mM does not inhibit Na.sub.v
channels, but can inhibit NMDA receptors, potentiate two-pore
domain potassium channels (K.sub.2P), potentiate glycine receptors
and potentiate GABA.sub.A receptors; wherein an anesthetic with a
molar water solubility below about 1.1 mM does not inhibit Na.sub.v
channels or inhibit NMDA receptors, but can potentiate two-pore
domain potassium channels (K.sub.2P), potentiate glycine receptors
and potentiate GABA.sub.A receptors; wherein an anesthetic with a
molar water solubility below about 0.26 mM does not inhibit
Na.sub.v channels, inhibit NMDA receptors or potentiate two-pore
domain potassium channel (K.sub.2P) currents, but can potentiate
glycine receptors and potentiate GABA.sub.A receptors; and wherein
an anesthetic with a molar water solubility below about 68 .mu.M
does not inhibit Na.sub.v channels, inhibit NMDA receptors,
potentiate two-pore domain potassium channel (K.sub.2P) currents,
or potentiate GABA.sub.A receptors but can potentiate glycine
receptors; thereby determining the specificity of an anesthetic for
an anesthetic-sensitive receptor.
44. The method of claim 43, wherein the anesthetic is selected from
the compounds administered in the methods of claim 6.
45. A method of modulating the specificity of an anesthetic for an
anesthetic-sensitive receptor comprising adjusting the molar water
solubility of the anesthetic to be above a predetermined water
solubility threshold concentration for an anesthetic-sensitive
receptor that the anesthetic can modulate or adjusting the molar
water solubility of the anesthetic to be below a predetermined
molar water solubility threshold concentration for an
anesthetic-sensitive receptor that the anesthetic cannot modulate;
wherein an anesthetic with a molar water solubility below about 1.2
mM does not inhibit Na.sub.v channels, but can inhibit NMDA
receptors, potentiate two-pore domain potassium channels
(K.sub.2P), potentiate glycine receptors and potentiate GABA.sub.A
receptors; wherein an anesthetic with a molar water solubility
below about 1.1 mM does not inhibit Na.sub.v channels or inhibit
NMDA receptors, but can potentiate two-pore domain potassium
channels (K.sub.2P), potentiate glycine receptors and potentiate
GABA.sub.A receptors; wherein an anesthetic with a molar water
solubility below about 0.26 mM does not inhibit Na.sub.v channels,
inhibit NMDA receptors or potentiate two-pore domain potassium
channel (K.sub.2P) currents, but can potentiate glycine receptors
and potentiate GABA.sub.A receptors; and wherein an anesthetic with
a molar water solubility below about 68 .mu.M does not inhibit
Na.sub.v channels, inhibit NMDA receptors, potentiate two-pore
domain potassium channel (K.sub.2P) currents, or potentiate
GABA.sub.A receptors but can potentiate glycine receptors; thereby
determining the specificity of an anesthetic for an
anesthetic-sensitive receptor.
46. The method claim 45, wherein the anesthetic is an inhalational
anesthetic.
47. The method of claim 45, wherein the anesthetic is selected from
the group consisting of halogenated alcohols, halogenated diethers,
halogenated dioxanes, halogenated dioxolanes, halogenated
cyclopentanes, halogenated cyclohexanes, halogenated
tetrahydrofurans and halogenated tetrahydropyrans, wherein the
anesthetic has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms do not
exceed the number of carbon atoms.
48. The method of claim 45, wherein the anesthetic is selected from
the compounds administered in the methods of any one of claims 6 to
32.
49. The method of claim 45, wherein the anesthetic is selected from
the group consisting of nonane, midazolam, diazepam, undecanol,
etomidate, 1,2-dichlorohexafluorocyclobutane, and analogs
thereof.
50. The method of claim 45, wherein the anesthetic is selected from
the group consisting of sevoflurane, propofol, ketamine,
isoflurane, enflurane, dizocilpine, desflurane, halothane,
cyclopropane, chloroform, 2,6-dimethylphenol, methoxyflurane,
diethyl ether, nitrous oxide, ethanol, and analogs thereof.
51. The method of claim 45, wherein the anesthetic is adjusted to
have a molar water solubility of less than about 1.1 mM and
potentiates GABA.sub.A receptors but does not inhibit NMDA
receptors.
52. The method of claim 45, wherein the anesthetic is adjusted to
have a molar water solubility of greater than about 1.1 mM and both
potentiates GABA.sub.A receptors and inhibits NMDA receptors.
53. The method of claim 45, wherein the anesthetic is an analog of
an inhalational anesthetic.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This patent application claims the benefit of U.S.
Provisional Patent Application No. 61/681,747, filed Aug. 10, 2012,
and of U.S. Provisional Patent Application No. 61/670,098, filed
Jul. 10, 2012, the contents of which are hereby incorporated herein
by reference in the entirety
FIELD OF THE INVENTION
[0003] The present invention provides methods for determining the
selectivity of an anesthetic for an anesthetic-sensitive receptor
by determining the molar water solubility of the anesthetic. The
invention further provides methods for modulating the selectivity
of an anesthetic for an anesthetic-sensitive receptor by altering
or modifying the anesthetic to have higher or lower water
solubility. The invention further provides methods of inducing
anesthesia in a subject by administering via the respiratory
pathways (e.g., via inhalational or pulmonary delivery) an
effective amount of an anesthetic compound identified according to
the present methods.
BACKGROUND OF THE INVENTION
[0004] Molecular Mechanisms of Anesthetic Action
[0005] All general anesthetics in common clinical use modulate
either three-transmembrane (TM3) ion channels (e.g., NMDA
receptors), four-transmembrane (TM4) ion channels (e.g., GABA.sub.A
receptors), or members of both ion channel superfamilies. Sonner,
et al., Anesth Analg (2003) 97:718-40. For example, many
structurally unrelated inhaled anesthetics potentiate GABA.sub.A
currents and inhibit NMDA currents. But why should a diverse group
of compounds all modulate unrelated ion channels? A highly specific
"induced fit" model between protein and ligand, as proposed for
enzyme-substrate binding, (Koshland, Proc Natl Acad Sci USA 1958;
44: 98-104) is problematic since it implies the conservation of
specific binding sites across non-homologous proteins to compounds
(i.e., anesthetics) not found in nature. Sonner, Anesth Analg
(2008) 107: 849-54. Moreover, promiscuous anesthetic actions on
disparate receptors typically occurs at drug concentrations 50-200
times the median effective concentration (EC50) at which modulation
of a single receptor class typically occurs, such as with etomidate
agonism of GABA.sub.A receptors (Tomlin et al., Anesthesiology
(1998) 88: 708-17; Hill-Venning, et al., Br J Pharmacol (1997) 120:
749-56; Belelli, et al., Br J Pharmacol (1996) 118: 563-76; Quast,
et al., J Neurochem (1983) 41:418-25; and Franks, Br J Pharmacol
2006; 147 Suppl 1: S72-81) or dizocilpine (MK-801) antagonism of
NMDA receptors. Wong, et al., Proc Natl Acad Sci USA (1986) 83:
7104-8; Ransom, et al., Brain Res (1988) 444: 25-32; and Sircar, et
al., Brain Res (1987) 435: 235-40. It is unknown what molecular
properties confer specificity for a single receptor (or members of
a single receptor superfamily) and what properties allow other
anesthetics to modulate multiple unrelated receptors. However,
since ion channel modulation is important to conferring desirable
anesthetic efficacy--as well as undesirable drug side effects--it
is desirable to know what factors influence anesthetic receptor
specificity in order to develop new and safer agents.
[0006] Anesthetics and Specific Ion Channel Targets
[0007] General anesthetics mediate central nervous system
depression through actions on cell membrane receptors and channels
which have a net hyperpolarizing effect on neurons. Sonner, et al.,
Anesth Analg (2003) 97:718-40; Grasshoff, et al., Eur J
Anaesthesiol (2005) 22: 467-70; Franks, Br J Pharmacol (2006) 147
Suppl 1: S72-81; 33; Hemmings, et al., Trends Pharmacol Sci (2005)
26: 503-10; and Forman, et al., Int Anesthesiol Clin (2008) 46:
43-53. Although anesthetics partition into cell membranes as a
function of lipid solubility, it is through competitive protein
binding that these agents most likely produce anesthetic effects.
In fact, general anesthetics have been shown to competitively
inhibit functions of membrane-free enzymes (Franks, et al., Nature
(1984) 310: 599-601), indicating that the lipid phase is not
essential for anesthetic modulation of protein function. Specific
high-affinity binding sites have been identified for some of these
anesthetics. For example, propofol (Jewett, et al., Anesthesiology
(1992) 77: 1148-54; Bieda, et al., J Neurophysiol (2004) 92:
1658-67; Peduto, et al., Anesthesiology 1991; 75: 1000-9; Sonner,
et al, Anesth Analg (2003) 96: 706-12; and Dong et al., Anesth
Analg (2002) 95: 907-14), etomidate (Flood, et al., Anesthesiology
(2000) 92: 1418-25; Zhong, et al., Anesthesiology 2008; 108:
103-12; O'Meara, et al., Neuroreport (2004) 15: 1653-6), and
thiopental (Jewett, et al., Anesthesiology (1992) 77: 1148-54;
Bieda, et al, J Neurophysiol (2004) 92: 1658-67; Yang, et al.,
Anesth Analg (2006) 102: 1114-20) all potently potentiate
GABA.sub.A receptor currents, and their anesthetic effects are
potently antagonized or prevented by GABA.sub.A receptor
antagonists, such as pictotoxin or bicuculline. Ketamine produces
anesthesia largely (but not entirely) through its antagonism of
NMDA receptors. Harrison et al., Br J Pharmacol (1985) 84: 381-91;
Yamamura, et al., Anesthesiology (1990) 72: 704-10; and Kelland, et
al., Physiol Behav (1993) 54: 547-54. Dexmedetomidine is a specific
.alpha.2 adrenoreceptor agonist that is antagonized by specific
.alpha.2 adrenoreceptor antagonists, such as atipamezole. Doze, et
al., Anesthesiology (1989) 71: 75-9; Karhuvaara, et al., Br J Clin
Pharmacol (1991) 31: 160-5; and Correa-Sales, et al.,
Anesthesiology (1992) 76: 948-52. It is probably not by coincidence
that anesthetics for which a single receptor contributes to most or
all of the anesthetic effect also have low aqueous ED50 values
(see, Table 1).
TABLE-US-00001 TABLE 1 Aqueous phase EC50 for several anesthetics.
Aqueous Anesthetic EC.sub.50 (.mu.M) Species Reference Propofol 2
Rat Tonner et al., Anesthesiology (1992) 77: 926-31 Ketamine 2
Human Flood, et al., Anesthesiology (2000) 92: 1418-25 Etomidate 3
Tadpole Tomlin, et al., Anesthesiology (1998) 88: 708-17
Dexmedetomidine 7 Tadpole Tonner, et al., Anesth Analg (1997) 84:
618-22 Thiopental 25 Human Flood, et al., Anesthesiology (2000) 92:
1418-25 Methoxyflurane 210 Tadpole Franks, et al., Br J Anaesth
(1993) 71: 65-76 Halothane 230 Tadpole Franks, et al., Br J Anaesth
(1993) 71: 65-76 Isoflurane 290 Tadpole Franks, et al., Br J
Anaesth (1993) 71: 65-76 Chloroform 1300 Tadpole Franks, et al., Br
J Anaesth (1993) 71: 65-76 Diethyl ether 25000 Tadpole Franks, et
al., Br J Anaesth (1993) 71: 65-76
[0008] Ion channel mutations, either in vitro or in vivo,
dramatically alter anesthetic sensitivity, not only for the very
potent and specific agents, but also for the inhaled anesthetics.
Several mutations in the GABA.sub.A (Hara, et al., Anesthesiology
2002; 97: 1512-20; Jenkins, et al., J Neurosci 2001; 21: RC136;
Krasowski, et al., Mol Pharmacol 1998; 53: 530-8; Scheller, et al.,
Anesthesiology 2001; 95: 123-31; Nishikawa, et al.,
Neuropharmacology 2002; 42: 337-45; Jenkins, et al.,
Neuropharmacology 2002; 43: 669-78; Jurd, et al., FASEB J 2003; 17:
250-2; Kash, et al., Brain Res 2003; 960: 36-41; Borghese, et al.,
J Pharmacol Exp Ther 2006; 319: 208-18; Drexler, et al.,
Anesthesiology 2006; 105: 297-304) or NMDA (Ogata, et al., J
Pharmacol Exp Ther (2006) 318: 434-43; Dickinson, et al.,
Anesthesiology 2007; 107: 756-67) receptor can decrease responses
to isoflurane, halothane, and other volatile anesthetics. Although
mutations that render receptors insensitive to anesthetics could
suggest a single site that is responsible for binding a specific
drug, it need not be the case. Most of these mutations are believed
to reside near lipid-water interfaces, either in amphiphilic
protein pockets (Bertaccini et al., Anesth Analg (2007) 104:
318-24; Franks, et al., Nat Rev Neurosci (2008) 9: 370-86) or near
the outer lipid membrane. It is possible that an anesthetic could
be excluded from its protein interaction site because of size.
However, it is also possible that the mutation substantially
increases (but does not entirely exclude) the number of
"non-specific" low-affinity anesthetic-protein interactions
necessary to modulate the receptor. In this case, modulation of the
mutant receptor will either only occur at anesthetic concentrations
in excess of the wild-type minimum alveolar concentration (MAC)
(Eger, et al., Anesthesiology (1965) 26: 756-63) or, if the drug is
insufficiently soluble at the active site to allow a sufficient
number of "non-specific" interactions with the mutant protein, no
receptor modulation will be possible even at saturating aqueous
drug concentrations.
[0009] Another argument for specific "induced fit" binding sites on
ion channels is the "cut-off" effect. For example, increasing the
carbon chain length of an alkanol increases lipid solubility and
anesthetic potency, as predicted by the Meyer-Overton hypothesis
(Overton CE: Studies of Narcosis. London, Chapman and Hall, 1991),
until a 12-carbon chain length (dodecanol) is reached (Alifimoff,
et al., Br J Pharmacol (1989) 96: 9-16). Alkanols with a longer
chain length were not anesthetics (hence, a "cut-off" effect at
C=13 carbons). However, the hydrocarbon chain length needed to
reach the cut-off effect is C=9 for alkanes (Liu, et al., Anesth
Analg (1993) 77: 12-8), C=2 for perfluorinated alkanes (Liu, et
al., Anesth Analg (1994) 79: 238-44), and C=3 for perfluorinated
methyl ethyl ethers (Koblin, et al., Anesth Analg (1999) 88:
1161-7). If size is essential to access a specific anesthetic
binding site, then why is the "cut-off" chain length not constant?
At the cellular level, straight-chain alcohols can maximally
inhibit NMDA receptor function up to octanol with complete cut-off
at C=10. But straight-chain 1, .OMEGA.-diols maximally inhibit NMDA
receptors up to decanol, with complete cut-off not observed until
C=16 (Peoples, et al., Mol Pharmacol (2002) 61: 169-76). Increasing
hydrocarbon chain length does not only increase molecular volume,
but also decreases water solubility. The cut-off effect therefore
refers to a minimum water solubility necessary to produce an
effect, rather than a maximum molecular size.
[0010] Anesthetics and Low-Affinity "Non-Specific" Ion Channel
Effects
[0011] At the tens of micromolar concentrations or less,
anesthetics most likely exert their effects on ion channels by
specific binding to relatively high-affinity sites on proteins to
induce a conformational change that alters ion conductance, either
alone or in the presence of another endogenous ligand. However,
these agents can still interact with other receptors (or the same
receptor at different sites) if present in higher concentrations.
For example, assume that two dissimilar receptors (R1 and R2) each
can exert an anesthetic effect. Assuming that efficacy of a drug at
R1=1, that R1 is able to produce a full anesthetic effect in
isolation, and that the EC99 of R1 is less than the EC1 of R2, then
this drug will produce anesthesia by selectively modulating R1.
However, if any of these assumptions is not true, then some
contribution of R2 will be required to produce an anesthetic effect
(FIG. 1).
[0012] Many injectable anesthetics seem to follow the example
described above. Propofol is a positive modulator of GABA.sub.A
receptor currents with an EC50 around 60 .mu.M (Hill-Venning, et
al., Br J Pharmacol (1997) 120: 749-56; Prince, et al., Biochem
Pharmacol (1992) 44: 1297-302; Orser, et al., J Neurosci (1994) 14:
7747-60; Reynolds, et al., Eur J Pharmacol (1996) 314: 151-6), and
propofol is believed to mediate the majority of its anesthetic
effects through potentiation of GABA.sub.A currents (Sonner, et al,
Anesth Analg (2003) 96: 706-12). However, propofol also inhibits
currents from the unrelated NMDA receptor with an 1050 of 160 .mu.M
(Orser, et al., Br J Pharmacol (1995) 116: 1761-8). Ketamine
produces anesthesia largely through antagonism of NMDA receptors,
which it inhibits with an IC50 of 14 .mu.M (Liu, et al., Anesth
Analg (2001) 92: 1173-81), although 365 .mu.M ketamine also
increases unrelated 4 transmembrane GABA.sub.A receptor currents by
56% (Lin, et al., J Pharmacol Exp Ther (1992) 263: 569-78). In
these cases, it seems plausible that 2 different types of
interactions (for high- vs. low-affinity responses) could occur on
a single receptor to produce the same qualitative effect. In
contrast, volatile inhaled anesthetics generally have little or no
effect on GABA.sub.A and NMDA receptors at aqueous phase
concentrations <50 .mu.M (Lin, et al., J Pharmacol Exp Ther
(1992) 263: 569-78; Moody, et al., Brain Res (1993) 615: 101-6;
Harris, et al., J Pharmacol Exp Ther (1993) 265: 1392-8; Jones, et
al., J Physiol (1992) 449: 279-93; Hall, et al., Br J Pharmacol
(1994) 112: 906-10). It is possible that these agents are not
specific ligands for any anesthetic-sensitive receptor that is
relevant to immobility; thus they may rely only on nonspecific
protein-ligand interactions that, in turn, may be reflected in the
higher aqueous phase concentrations of these agents required for
anesthesia (Table 1).
BRIEF SUMMARY OF THE INVENTION
[0013] In one aspect, the invention provides methods of inducing
anesthesia in a subject. In some embodiments, the methods comprise
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
I:
##STR00001## [0014] wherein: [0015] n is 0-4, [0016] R.sup.1 is H;
[0017] R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently
are selected from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and
C.sub.2X.sub.5; and [0018] wherein X is a halogen, the compound
having vapor pressure of at least 0.1 atmospheres (76 mmHg) at
25.degree. C., and the number of hydrogen atoms in Formula I do not
exceed the number of carbon atoms, thereby inducing anesthesia in
the subject. In various embodiments, X is a halogen selected from
the group consisting of F, Cl, Br and I. In some embodiments, X is
F. In some embodiments, R.sup.1 is selected from H, CH.sub.2OH,
CHFOH and CF.sub.2OH, CHClOH, CCl.sub.2OH and CFClOH. In some
embodiments, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F. In some embodiments, the compound is selected
from the group consisting of: a) Methanol,
1-fluoro-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]-(CAS
#1351959-82-4); b) 1-Butanol,
4,4,4-trifluoro-3,3-bis(trifluoromethyl)-(CAS#14115-49-2); c)
1-Butanol, 1,1,2,2,3,3,4,4,4-nonafluoro-(CAS#3056-01-7); d)
1-Butanol,
2,2,3,4,4,4-hexafluoro-3-(trifluoromethyl)-(CAS#782390-93-6); e)
1-Butanol,
3,4,4,4-tetrafluoro-3-(trifluoromethyl)-(CAS#90999-87-4); f)
1-Pentanol, 1,1,4,4,5,5,5-heptafluoro-(CAS#313503-66-1); and g)
1-Pentanol,
1,1,2,2,3,3,4,4,5,5,5-undecafluoro-(CAS#57911-98-5).
[0019] In a further aspect, the invention provides methods of
inducing anesthesia in a subject. In some embodiments, the methods
comprise administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
II:
##STR00002## [0020] wherein: [0021] n is 1-3, [0022] R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X and C.sub.2X.sub.5; and [0023] wherein X is a halogen,
the compound having vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms in Formula
II do not exceed the number of carbon atoms, thereby inducing
anesthesia in the subject. In various embodiments, X is a halogen
selected from the group consisting of F, Cl, Br and I. In some
embodiments, X is F. In some embodiments, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F. In some embodiments, the compound is selected
from the group consisting of: a) Ethane,
1,1,2-trifluoro-1,2-bis(trifluoromethoxy)-(CAS#362631-92-3); b)
Ethane,
1,1,1,2-tetrafluoro-2,2-bis(trifluoromethoxy)-(CAS#115395-39-6); c)
Ethane,
1-(difluoromethoxy)-1,1,2,2-tetrafluoro-2-(trifluoromethoxy)-(CAS-
#40891-98-3); d) Ethane,
1,1,2,2-tetrafluoro-1,2-bis(trifluoromethoxy)-(CAS#378-11-0); e)
Ethane, 1,2-difluoro-1,2-bis(trifluoromethoxy)-(CAS#362631-95-6);
f) Ethane, 1,2-bis(trifluoromethoxy)-(CAS#1683-90-5); g) Propane,
1,1,3,3-tetrafluoro-1,3-bis(trifluoromethoxy)-(CAS#870715-97-2); h)
Propane, 2,2-difluoro-1,3-bis(trifluoromethoxy)-(CAS#156833-18-0);
i) Propane,
1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethoxy)-(CAS#133640-
-19-4; j) Propane,
1,1,1,3,3,3-hexafluoro-2-(fluoromethoxymethoxy)-(CAS#124992-92-3);
and k) Propane,
1,1,1,2,3,3-hexafluoro-3-methoxy-2-(trifluoromethoxy)-(CAS#10415-
9-55-9).
[0024] In another aspect, the invention provides methods of
inducing anesthesia in a subject. In some embodiments, the methods
comprise administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
III:
##STR00003## [0025] wherein: [0026] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are
selected from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and
C.sub.2X.sub.5; and [0027] wherein X is a halogen, the compound has
a vapor pressure of at least 0.1 atmospheres (76 mmHg) at
25.degree. C., and the number of hydrogen atoms of Formula III do
not exceed the number of carbon atoms, thereby inducing anesthesia
in the subject. In various embodiments, X is a halogen selected
from the group consisting of F, Cl, Br and I. In some embodiments,
X is F. In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are selected
from H, F, Cl, Br, I, CF.sub.3, CHF.sub.2, CH.sub.2F,
C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, C.sub.2Cl.sub.5,
CCl.sub.2F, CClF.sub.2, CHClF, C.sub.2ClF.sub.4,
C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2, and
C.sub.2Cl.sub.4F. In some embodiments, the compound is selected
from the group consisting of: a) 1,4-Dioxane,
2,2,3,3,5,6-hexafluoro-(CAS#362631-99-0); b) 1,4-Dioxane,
2,3-dichloro-2,3,5,5,6,6-hexafluoro-(CAS#135871-00-0); c)
1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-, trans-(9CI)
(CAS#56625-45-7); d) 1,4-Dioxane,
2,3-dichloro-2,3,5,5,6,6-hexafluoro-, cis-(9CI) (CAS#56625-44-6);
e) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro-(CAS#56269-26-2); f)
1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-(CAS#56269-25-1); g)
1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, trans-(9CI) (CAS#34206-83-2);
h) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-, cis-(9CI)
(CAS#34181-52-7); i) p-Dioxane, 2,2,3,5,5,6-hexafluoro-,
trans-(8CI) (CAS#34181-51-6); j) 1,4-Dioxane,
2,2,3,5,6,6-hexafluoro-, cis-(9CI) (CAS#34181-50-5); k) p-Dioxane,
2,2,3,5,6,6-hexafluoro-, trans-(8CI) (CAS#34181-49-2); l)
1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, (5R,6S)-rel-(CAS#34181-48-1);
m) 1,4-Dioxane, 2,2,3,3,5,5,6-heptafluoro-(CAS#34118-18-8); and n)
1,4-Dioxane, 2,2,3,3,5,5,6,6-octafluoro-(CAS#32981-22-9).
[0028] In another aspect, the invention provides methods of
inducing anesthesia in a subject. In some embodiments, the methods
comprise administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
IV:
##STR00004## [0029] wherein: [0030] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 independently are selected from H, X,
CX.sub.3, CHX.sub.2, CH.sub.2X and C.sub.2X.sub.5; and [0031]
wherein X is a halogen, the compound has a vapor pressure of at
least 0.1 atmospheres (76 mmHg) at 25.degree. C., and the number of
hydrogen atoms of Formula IV do not exceed the number of carbon
atoms, thereby inducing anesthesia in the subject. In various
embodiments, X is a halogen selected from the group consisting of
F, Cl, Br and I. In some embodiments, X is F. In some embodiments,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F. In some embodiments, the compound is selected
from the group consisting of: a) 1,3-Dioxolane,
2,4,4,5-tetrafluoro-5-(trifluoromethyl)-(CAS#344303-08-8); b)
1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-(CAS#344303-05-5); c)
1,3-Dioxolane,
4,4,5,5-tetrafluoro-2-(trifluoromethyl)-(CAS#269716-57-6); d)
1,3-Dioxolane,
4-chloro-2,2,4-trifluoro-5-(trifluoromethyl)-(CAS#238754-29-5); e)
1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-, trans-(9CI) (CAS
#162970-78-7); f) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-,
cis-(9CI) (CAS#162970-76-5); g) 1,3-Dioxolane,
4-chloro-2,2,4,5,5-pentafluoro-(CAS#139139-68-7); h) 1,3-Dioxolane,
4,5-dichloro-2,2,4,5-tetrafluoro-(CAS#87075-00-1); i)
1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-,
trans-(9CI) (CAS#85036-66-4); j) 1,3-Dioxolane,
2,4,4,5-tetrafluoro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#85036-65-3); k) 1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-, trans-(9CI)
(CAS#85036-60-8); l) 1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#85036-57-3); m) 1,3-Dioxolane,
2,2-dichloro-4,4,5,5-tetrafluoro-(CAS#85036-55-1); n)
1,3-Dioxolane,
4,4,5-trifluoro-5-(trifluoromethyl)-(CAS#76492-99-4); o)
1,3-Dioxolane,
4,4-difluoro-2,2-bis(trifluoromethyl)-(CAS#64499-86-1); p)
1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-, cis-(9CI)
(CAS#64499-85-0); q) 1,3-Dioxolane,
4,5-difluoro-2,2-bis(trifluoromethyl)-, trans-(9CI)
(CAS#64499-66-7); r) 1,3-Dioxolane,
4,4,5-trifluoro-2,2-bis(trifluoromethyl)-(CAS#64499-65-6); s)
1,3-Dioxolane,
2,4,4,5,5-pentafluoro-2-(trifluoromethyl)-(CAS#55135-01-8); t)
1,3-Dioxolane, 2,2,4,4,5,5-hexafluoro-(CAS#21297-65-4); and u)
1,3-Dioxolane,
2,2,4,4,5-pentafluoro-5-(trifluoromethyl)-(CAS#19701-22-5).
[0032] In another aspect, the invention provides methods of
inducing anesthesia in a subject. In some embodiments, the methods
comprise administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
V:
##STR00005## [0033] wherein: [0034] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X and C.sub.2X.sub.5; and [0035] wherein X is a halogen,
the compound has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms of Formula
V do not exceed the number of carbon atoms, thereby inducing
anesthesia in the subject. In various embodiments, X is a halogen
selected from the group consisting of F, Cl, Br and I. In some
embodiments, X is F. In some embodiments, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and
R.sup.10 independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F. In some embodiments, the compound is selected
from the group consisting of: a) Cyclopentane,
5-chloro-1,1,2,2,3,3,4,4-octafluoro-(CAS#362014-70-8); b)
Cyclopentane, 1,1,2,2,3,4,4,5-octafluoro-(CAS#773-17-1); c)
Cyclopentane, 1,1,2,2,3,3,4,5-octafluoro-(CAS#828-35-3); d)
Cyclopentane, 1,1,2,3,3,4,5-heptafluoro-(CAS#3002-03-7); e)
Cyclopentane, 1,1,2,2,3,3,4,4-octafluoro-(CAS#149600-73-7); f)
Cyclopentane, 1,1,2,2,3,4,5-heptafluoro-(CAS#1765-23-7); g)
Cyclopentane, 1,1,2,3,4,5-hexafluoro-(CAS#699-38-7); h)
Cyclopentane, 1,1,2,2,3,3,4-heptafluoro-(CAS#15290-77-4); i)
Cyclopentane, 1,1,2,2,3,4-hexafluoro-(CAS#199989-36-1); j)
Cyclopentane, 1,1,2,2,3,3-hexafluoro-(CAS#123768-18-3); and k)
Cyclopentane, 1,1,2,2,3-pentafluoro-(CAS#1259529-57-1). In some
embodiments, the compound is selected from the group consisting of:
c) Cyclopentane, 1,1,2,2,3,3,4,5-octafluoro-(CAS#828-35-3); e)
Cyclopentane, 1,1,2,2,3,3,4,4-octafluoro-(CAS#149600-73-7); and h)
Cyclopentane, 1,1,2,2,3,3,4-heptafluoro-(CAS#15290-77-4).
[0036] In another aspect, the invention provides methods of
inducing anesthesia in a subject. In some embodiments, the methods
comprise administering to the subject via the respiratory system an
effective amount of 1,1,2,2,3,3,4,4-octafluoro-cyclohexane
(CAS#830-15-9), thereby inducing anesthesia in the subject.
[0037] In another aspect, the invention provides methods of
inducing anesthesia in a subject. In some embodiments, the methods
comprise administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds of Formula
VI:
##STR00006## [0038] wherein: [0039] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are
selected from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and
C.sub.2X.sub.5; and [0040] wherein X is a halogen, the compound has
a vapor pressure of at least 0.1 atmospheres (76 mmHg) at
25.degree. C., and the number of hydrogen atoms of Formula VI do
not exceed the number of carbon atoms, thereby inducing anesthesia
in the subject. In various embodiments, X is a halogen selected
from the group consisting of F, Cl, Br and I. In some embodiments,
X is F. In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are selected
from H, F, Cl, Br, I, CF.sub.3, CHF.sub.2, CH.sub.2F,
C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, C.sub.2Cl.sub.5,
CCl.sub.2F, CClF.sub.2, CHClF, C.sub.2ClF.sub.4,
C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2, and
C.sub.2Cl.sub.4F. In some embodiments, the compound is selected
from the group consisting of: a) Furan,
2,3,4,4-tetrafluorotetrahydro-2,3-bis(trifluoromethyl)-(CAS#634191-25-6);
b) Furan,
2,2,3,3,4,4,5-heptafluorotetrahydro-5-(trifluoromethyl)-(CAS#37-
7-83-3); c) Furan,
2,2,3,3,4,5,5-heptafluorotetrahydro-4-(trifluoromethyl)-(CAS#374-53-8);
d) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2a,3.beta.,4a)-(9CI) (CAS#133618-53-8); e) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2a,3a,4.beta.)-(CAS#133618-52-7); f) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2.alpha.,3.beta.,4.alpha.)-(9CI) (CAS#133618-53-8); g) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2.alpha.,3.alpha.,4.beta.)-(9CI) (CAS#133618-52-7); h) Furan,
2,2,3,3,5,5-hexafluorotetrahydro-4-(trifluoromethyl)-(CAS#61340-70-3);
i) Furan,
2,3-difluorotetrahydro-2,3-bis(trifluoromethyl)-(CAS#634191-26-7);
j) Furan,
2-chloro-2,3,3,4,4,5,5-heptafluorotetrahydro-(CAS#1026470-51-8)- ;
k) Furan,
2,2,3,3,4,4,5-heptafluorotetrahydro-5-methyl-(CAS#179017-83-5); l)
Furan, 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-,
trans-(9CI) (CAS#133618-59-4); and m) Furan,
2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#133618-49-2).
[0041] In another aspect, the invention provides methods of
inducing anesthesia in a subject. In some embodiments, the methods
comprise administering to the subject via the respiratory system an
effective amount of a compound or mixture of compounds of Formula
VII:
##STR00007## [0042] wherein: [0043] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X, and C.sub.2X.sub.5; and [0044] wherein X is a halogen,
the compound has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms of Formula
VII do not exceed the number of carbon atoms, thereby inducing
anesthesia in the subject. In various embodiments, X is a halogen
selected from the group consisting of F, Cl, Br and I. In some
embodiments, X is F. In some embodiments, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and
R.sup.10 independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F. In some embodiments, the compound is selected
from the group consisting of: a) 2H-Pyran,
2,2,3,3,4,5,5,6,6-nonafluorotetrahydro-4-(CAS #71546-79-7); b)
2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-(trifluoromethyl)-(CAS#356-47-8)-
; c) 2H-Pyran,
2,2,3,3,4,4,5,6,6-nonafluorotetrahydro-5-(trifluoromethyl)-(CAS#61340-74--
7); d) 2H-Pyran,
2,2,6,6-tetrafluorotetrahydro-4-(trifluoromethyl)-(CAS#657-48-7);
e) 2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-methyl-(CAS#874634-55--
6);
f) Perfluorotetrahydropyran (CAS#355-79-3);
[0045] g) 2H-Pyran, 2,2,3,3,4,5,5,6-octafluorotetrahydro-,
(4R,6S)-rel-(CAS#362631-93-4); and h) 2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-(CAS#65601-69-6).
[0046] In various embodiments, the compound has a molar water
solubility of less than about 1.1 mM and greater than about 0.016
mM. In various embodiments, the compound potentiates GABA.sub.A
receptors, but does not inhibit NMDA receptors.
[0047] In some embodiments, the subject is a mammal. In some
embodiments, the subject is a human.
[0048] In a further aspect, the invention provides compositions
comprising a compound or a mixture of compounds used in the above
and herein described methods, wherein the composition is formulated
for inhalational or pulmonary delivery of the compound or mixture
of compounds.
[0049] In a further aspect, the invention provides methods of
selecting an anesthetic that preferentially activates or
potentiates GABA.sub.A receptors without inhibiting NMDA receptors.
In some embodiments, the methods comprise:
[0050] a) determining the molar water solubility of the anesthetic;
and
[0051] b) selecting an anesthetic with a molar water solubility
below about 1.1 mM,
wherein the anesthetic selectively potentiates GABA.sub.A receptors
and does not inhibit NMDA receptors, whereby an anesthetic that
preferentially activates or potentiates GABA.sub.A receptors
without inhibiting NMDA receptors is selected. In various
embodiments, the anesthetic is an inhalational anesthetic. In some
embodiments, the anesthetic is selected from the group consisting
of halogenated alcohols, halogenated diethers, halogenated
dioxanes, halogenated dioxolanes, halogenated cyclopentanes,
halogenated cyclohexanes, halogenated tetrahydrofurans and
halogenated tetrahydropyrans, wherein the anesthetic has a vapor
pressure of at least 0.1 atmospheres (76 mmHg) at 25.degree. C.,
and the number of hydrogen atoms do not exceed the number of carbon
atoms. In some embodiments, the anesthetic is selected from the
compounds administered in the methods described above and herein.
In some embodiments, the anesthetic is selected from the group
consisting of nonane, midazolam, diazepam, undecanol, etomidate,
1,2 dichlorohexafluorocyclobutane, and analogs thereof.
[0052] In a related aspect, the invention provides methods of
selecting an anesthetic that both potentiates GABA.sub.A receptors
and inhibits NMDA receptors. In some embodiments, the methods
comprise:
[0053] a) determining the molar water solubility of the anesthetic;
and
[0054] b) selecting an anesthetic with a molar water solubility
above about 1.1 mM,
wherein the anesthetic both potentiates GABA.sub.A receptors and
inhibits NMDA receptors, whereby an anesthetic that both
potentiates GABA.sub.A receptors and inhibits NMDA receptors is
selected. In various embodiments, the anesthetic is an inhalational
anesthetic. In some embodiments, the anesthetic is selected from
the group consisting of halogenated alcohols, halogenated diethers,
halogenated dioxanes, halogenated dioxolanes, halogenated
cyclopentanes, halogenated cyclohexanes, halogenated
tetrahydrofurans and halogenated tetrahydropyrans, wherein the
anesthetic has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms do not
exceed the number of carbon atoms. In some embodiments, the
anesthetic is selected from the compounds administered in the
methods described above and herein. In some embodiments, the
anesthetic is selected from the group consisting of sevoflurane,
propofol, ketamine, isoflurane, enflurane, dizocilpine, desflurane,
halothane, cyclopropane, chloroform, 2,6-dimethylphenol,
methoxyflurane, diethyl ether, nitrous oxide, ethanol, and analogs
thereof.
[0055] In another aspect, the invention of determining the
specificity of an anesthetic for an anesthetic-sensitive receptor
comprising determining whether the molar water solubility of the
anesthetic is above or below a predetermined solubility threshold
concentration for an anesthetic-sensitive receptor,
[0056] wherein an anesthetic with a molar water solubility below
about 1.2 mM does not inhibit Na.sub.v channels, but can inhibit
NMDA receptors, potentiate two-pore domain potassium channels
(K.sub.2P), potentiate glycine receptors and potentiate GABA.sub.A
receptors;
[0057] wherein an anesthetic with a molar water solubility below
about 1.1 mM does not inhibit Na.sub.v channels or inhibit NMDA
receptors, but can potentiate two-pore domain potassium channels
(K.sub.2P), potentiate glycine receptors and potentiate GABA.sub.A
receptors;
[0058] wherein an anesthetic with a molar water solubility below
about 0.26 mM does not inhibit Na.sub.v channels, inhibit NMDA
receptors or potentiate two-pore domain potassium channel
(K.sub.2P) currents, but can potentiate glycine receptors and
potentiate GABA.sub.A receptors; and
[0059] wherein an anesthetic with a molar water solubility below
about 68 .mu.M does not inhibit Na.sub.v channels, inhibit NMDA
receptors, potentiate two-pore domain potassium channel (K.sub.2P)
currents, or potentiate GABA.sub.A receptors but can potentiate
glycine receptors; thereby determining the specificity of an
anesthetic for an anesthetic-sensitive receptor. In various
embodiments, the anesthetic is an inhalational anesthetic. In some
embodiments, the anesthetic is selected from the group consisting
of halogenated alcohols, halogenated diethers, halogenated
dioxanes, halogenated dioxolanes, halogenated cyclopentanes,
halogenated cyclohexanes, halogenated tetrahydrofurans and
halogenated tetrahydropyrans, wherein the anesthetic has a vapor
pressure of at least 0.1 atmospheres (76 mmHg) at 25.degree. C.,
and the number of hydrogen atoms do not exceed the number of carbon
atoms. In some embodiments, the anesthetic is selected from the
compounds administered in the methods described above and
herein.
[0060] In another aspect, the invention provides methods of
modulating the specificity of an anesthetic for an
anesthetic-sensitive receptor. In some embodiments, the methods
comprise adjusting the molar water solubility of the anesthetic to
be above a predetermined water solubility threshold concentration
for an anesthetic-sensitive receptor that the anesthetic can
modulate or adjusting the molar water solubility of the anesthetic
to be below a predetermined molar water solubility threshold
concentration for an anesthetic-sensitive receptor that the
anesthetic cannot modulate;
[0061] wherein an anesthetic with a molar water solubility below
about 1.2 mM does not inhibit Na.sub.v channels, but can inhibit
NMDA receptors, potentiate two-pore domain potassium channels
(K.sub.2P), potentiate glycine receptors and potentiate GABA.sub.A
receptors;
[0062] wherein an anesthetic with a molar water solubility below
about 1.1 mM does not inhibit Na.sub.v channels or inhibit NMDA
receptors, but can potentiate two-pore domain potassium channels
(K.sub.2P), potentiate glycine receptors and potentiate GABA.sub.A
receptors;
[0063] wherein an anesthetic with a molar water solubility below
about 0.26 mM does not inhibit Na.sub.v channels, inhibit NMDA
receptors or potentiate two-pore domain potassium channel
(K.sub.2P) currents, but can potentiate glycine receptors and
potentiate GABA.sub.A receptors; and
[0064] wherein an anesthetic with a molar water solubility below
about 68 .mu.M does not inhibit Na.sub.v channels, inhibit NMDA
receptors, potentiate two-pore domain potassium channel (K.sub.2P)
currents, or potentiate GABA.sub.A receptors but can potentiate
glycine receptors; thereby determining the specificity of an
anesthetic for an anesthetic-sensitive receptor. In various
embodiments, the anesthetic is an inhalational anesthetic or an
analog thereof. In some embodiments, the anesthetic is selected
from the group consisting of halogenated alcohols, halogenated
diethers, halogenated dioxanes, halogenated dioxolanes, halogenated
cyclopentanes, halogenated cyclohexanes, halogenated
tetrahydrofurans and halogenated tetrahydropyrans, wherein the
anesthetic has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms do not
exceed the number of carbon atoms. In some embodiments, the
anesthetic is selected from the compounds administered in the
methods described above and herein. In some embodiments, the
anesthetic is selected from the group consisting of nonane,
midazolam, diazepam, undecanol, etomidate,
1,2-dichlorohexafluorocyclobutane, and analogs thereof. In some
embodiments, the anesthetic is selected from the group consisting
of sevoflurane, propofol, ketamine, isoflurane, enflurane,
dizocilpine, desflurane, halothane, cyclopropane, chloroform,
2,6-dimethylphenol, methoxyflurane, diethyl ether, nitrous oxide,
ethanol, and analogs thereof. In some embodiments, the anesthetic
is adjusted to have a molar water solubility of less than about 1.1
mM and potentiates GABA.sub.A receptors but does not inhibit NMDA
receptors. In some embodiments, the anesthetic is adjusted to have
a molar water solubility of greater than about 1.1 mM and both
potentiates GABA.sub.A receptors and inhibits NMDA receptors.
DEFINITIONS
[0065] The term "inhalational anesthetic" refers to gases or vapors
that possess anesthetic qualities that are administered by
breathing through an anesthesia mask or ET tube connected to an
anesthetic machine. Exemplary inhalational anesthetics include
without limitation volatile anesthetics (halothane, isoflurane,
sevoflurane and desflurane) and the gases (ethylene, nitrous oxide
and xenon).
[0066] The term "injectable anesthetic or sedative drug" refers to
anesthetics or sedatives that can be injected under the skin via a
hypodermic needle and syringe and that through actions on nerves in
the brain or spinal cord can either render an individual insensible
to painful stimuli, or decrease an individual's perceived sensation
of painful stimuli, or induce within an individual an amnestic
and/or calming effect.
[0067] The term "anesthetic-sensitive receptor" refers to a cell
membrane protein that binds to an anesthetic agent and whose
function is modulated by the binding of that anesthetic agent.
Anesthetic-sensitive receptors are usually ion channels or cell
membrane that are indirectly linked to ion channels via second
messenger systems (such as G-proteins and tyrosine kinases) and can
have 2, 3, 4, or 7 transmembrane regions. Such receptors can be
comprised of 2 or more subunits and function as part of a protein
complex. Activation or inhibition of these receptors results in
either a direct change in ion permeability across the cell membrane
that alters the cell resting membrane potential, or alters the
response of the cell receptor to its endogenous ligand in such a
way that the change in ion permeability and cell membrane potential
normally elicited by the endogenous ligand is changed. Exemplary
anesthetic-sensitive receptors include gamma-aminobutyric acid
(GABA) receptors, N-methyl-D-aspartate (NMDA) receptors,
voltage-gated sodium ion channels, voltage-gated potassium ion
channels, two-pore domain potassium channels, adrenergic receptors,
acetylcholine receptors, glycine and opioid receptors.
[0068] The term "effective amount" or "pharmaceutically effective
amount" refer to the amount and/or dosage, and/or dosage regime of
one or more compounds necessary to bring about the desired result
e.g., an amount sufficient to effect anesthesia, render the subject
unconscious and/or immobilize the subject.
[0069] As used herein, the term "pharmaceutically acceptable"
refers to a material, such as a carrier or diluent, which does not
abrogate the biological activity or properties of the compound
useful within the invention, and is relatively non-toxic, i.e., the
material may be administered to an individual without causing
undesirable biological effects or interacting in a deleterious
manner with any of the components of the composition in which it is
contained.
[0070] As used herein, the language "pharmaceutically acceptable
salt" refers to a salt of the administered compound prepared from
pharmaceutically acceptable non-toxic acids and bases, including
inorganic acids, inorganic bases, organic acids, inorganic bases,
solvates, hydrates, and clathrates thereof.
[0071] As used herein, the term "composition" or "pharmaceutical
composition" refers to a mixture of at least one compound useful
within the invention with a pharmaceutically acceptable carrier.
The pharmaceutical composition facilitates administration of the
compound to a subject.
[0072] The phrase "cause to be administered" refers to the actions
taken by a medical professional (e.g., a physician), or a person
controlling medical care of a subject, that control and/or permit
the administration of the agent(s)/compound(s) at issue to the
subject. Causing to be administered can involve diagnosis and/or
determination of an appropriate therapeutic or prophylactic
regimen, and/or prescribing particular agent(s)/compounds for a
subject. Such prescribing can include, for example, drafting a
prescription form, annotating a medical record, and the like.
[0073] The terms "patient," "individual," "subject" interchangeably
refer to any mammal, e.g., a human or non-human mammal, e.g., a
non-human primate, a domesticated mammal (e.g., canine, feline), an
agricultural mammal (e.g., equine, bovine, ovine, porcine), or a
laboratory mammal (e.g., rattus, murine, lagomorpha, hamster).
[0074] The term "molar water solubility" refers to the calculated
or measured number of moles per liter of a compound present at a
saturated concentration in pure water at 25.degree. C. and at
pH=7.0.
[0075] The term "solubility cut-off value" refers to the threshold
water solubility concentration of an anesthetic compound that can
activate a particular anesthetic-sensitive receptor. If the water
solubility of the anesthetic agent is below the solubility cut-off
value for a particular anesthetic-sensitive receptor, then the
agent will not activate that receptor. If the water solubility of
the anesthetic agent is above the solubility cut-off value for a
particular anesthetic-sensitive receptor, then the agent can, but
need not, activate that receptor.
[0076] The term "alkyl", by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain hydrocarbon radical, having the number of carbon atoms
designated (i.e. C.sub.1-8 means one to eight carbons). Examples of
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
and the like. For each of the definitions herein (e.g., alkyl,
alkoxy, alkylamino, alkylthio, alkylene, haloalkyl), when a prefix
is not included to indicate the number of main chain carbon atoms
in an alkyl portion, the radical or portion thereof will have 24 or
fewer, for example, 20, 18, 16, 14, 12, 10, 8, 6 or fewer, main
chain carbon atoms.
[0077] The term "alkylene" by itself or as part of another
substituent means an unsaturated hydrocarbon chain containing 1 or
more carbon-carbon double bonds. Typically, an alkyl (or alkylene)
group will have from 1 to 24 carbon atoms, with those groups having
10 or fewer carbon atoms being preferred in the present invention.
A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or
alkylene group, generally having four or fewer carbon atoms.
[0078] The term "cycloalkyl" refers to hydrocarbon rings having the
indicated number of ring atoms (e.g., C.sub.3-6cycloalkyl) and
being fully saturated or having no more than one double bond
between ring vertices. One or two C atoms may optionally be
replaced by a carbonyl. "Cycloalkyl" is also meant to refer to
bicyclic and polycyclic hydrocarbon rings such as, for example,
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. When a prefix is
not included to indicate the number of ring carbon atoms in a
cycloalkyl, the radical or portion thereof will have 8 or fewer
ring carbon atoms.
[0079] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
Additionally, for dialkylamino groups, the alkyl portions can be
the same or different and can also be combined to form a 3 to 8
membered ring with the nitrogen atom to which each is attached.
Accordingly, a group represented as --NR.sup.aRb is meant to
include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the
like.
[0080] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "C.sub.1-4 haloalkyl" is mean to include
trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,
3-bromopropyl, and the like.
[0081] The term "aryl" means a monovalent monocyclic, bicyclic or
polycyclic aromatic hydrocarbon radical of 5 to 14 ring atoms which
is unsubstituted or substituted independently with one to four
substituents, preferably one, two, or three substituents selected
from alkyl, cycloalkyl, cycloalkyl-alkyl, halo, cyano, hydroxy,
alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino,
haloalkyl, haloalkoxy, heteroalkyl, COR (where R is hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl cut, phenyl or phenylalkyl,
aryl or arylalkyl), --(CR'R'').sub.n--COOR (where n is an integer
from 0 to 5, R' and R'' are independently hydrogen or alkyl, and R
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl cut, phenyl or
phenylalkyl aryl or arylalkyl) or --(CR'R'').sub.n--CONR.sup.aRb
(where n is an integer from 0 to 5, R' and R'' are independently
hydrogen or alkyl, and R.sup.a and R.sup.b are, independently of
each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or
phenylalkyl, aryl or arylalkyl). More specifically the term aryl
includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and
2-naphthyl, and the substituted forms thereof. Similarly, the term
"heteroaryl" refers to those aryl groups wherein one to five
heteroatoms or heteroatom functional groups have replaced a ring
carbon, while retaining aromatic properties, e.g., pyridyl,
quinolinyl, quinazolinyl, thienyl, and the like. The heteroatoms
are selected from N, O, and S, wherein the nitrogen and sulfur
atoms are optionally oxidized, and the nitrogen atom(s) are
optionally quaternized. A heteroaryl group can be attached to the
remainder of the molecule through a heteroatom. Non-limiting
examples of aryl groups include phenyl, naphthyl and biphenyl,
while non-limiting examples of heteroaryl groups include pyridyl,
pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl,
benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,
benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl,
indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl,
pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl,
benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl,
isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,
pyrrolyl, thiazolyl, furyl, thienyl and the like. For brevity, the
term aryl, when used in combination with other radicals (e.g.,
aryloxy, arylalkyl) is meant to include both aryl groups and
heteroaryl groups as described above.
[0082] Substituents for the aryl groups are varied and are
generally selected from: -halogen, --OR', --OC(O)R', --NR'R'',
--SR', --R', --CN, --NO.sub.2, --CO.sub.2R', --CONR'R'', --C(O)R',
--OC(O)NR'R'', --NR''C(O)R', --NR''C(O).sub.2R',
--NR'--C(O)NR''R''', --NH--C(NH.sub.2).dbd.NH,
--NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NR'S(O).sub.2R'', --N.sub.3,
perfluoro(C.sub.1-4)alkoxy, and perfluoro(C.sub.1-4)alkyl, in a
number ranging from zero to the total number of open valences on
the aromatic ring system; and where R', R'' and R''' are
independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.3-6
cycloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl unsubstituted aryl
and heteroaryl, (unsubstituted aryl)-C.sub.1-4 alkyl, and
unsubstituted aryloxy-C.sub.1-4 alkyl.
[0083] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CH.sub.2).sub.q--U--, wherein T and U are
independently --NH--, --CH.sub.2-- or a single bond, and q is an
integer of from 0 to 2. Alternatively, two of the substituents on
adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B--, wherein A and B are independently
--CH.sub.2--, --NH--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 3. One of the single bonds of the new ring so formed may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CH.sub.2).sub.s--X--(CH.sub.2).sub.t--, where s and t are
independently integers of from 0 to 3, and X is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituent R' in --NR'-- and --S(O).sub.2NR'-- is selected from
hydrogen or unsubstituted C.sub.1-6 alkyl.
[0084] As used herein, the term "heteroatom" is meant to include
oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
BRIEF DESCRIPTION OF THE DRAWINGS
[0085] FIG. 1 illustrates a diagram showing the effect of drug dose
on the percent contribution to MAC of 2 anesthetic-sensitive
receptors (R1 and R2). The drug shows high-affinity for R1, but is
unable to produce an anesthetic effect by itself. A small
contribution from low-affinity interactions with R2 is necessary to
produce a 100% anesthetic effect (MAC).
[0086] FIG. 2 illustrates a summary of ion channel modulation as a
function of calculated anesthetic molar solubility in unbuffered
water at 25.degree. C. (values from SciFinder Scholar). Drugs that
modulate 4-transmembrane receptors (TM4) or neither receptor type
are shown as open circles (.smallcircle., A-F) below the dotted
horizontal solubility line. Drugs that modulate both
3-transmembrane (TM3) and TM4 receptors are shown as small black
circles ( , G-U) above the dotted horizontal solubility line.
A=nonane, B=midazolam (Nistri, et al., Neurosci Lett (1983)
39:199-204), C=diazepam (Macdonald, et al., Nature (1978)
271:563-564), D=undecanol (Dildy-Mayfield, et al., Br J Pharmacol
(1996) 118:378-384), E=etomidate (Flood, et al., Anesthesiology
(2000) 92:1418-1425), F=1,2-dichlorohexafluorocyclobutane (Kendig,
et al., Eur J Pharmacol (1994) 264:427-436), G=sevoflurane
(Jenkins, et al., Anesthesiology 1999; 90:484-491; Krasowski, Br J
Pharmacol (2000) 129:731-743; Hollmann, Anesth Analg (2001)
92:1182-1191, Nishikawa, et al., Anesthesiology (2003) 99:678-684),
H=propofol (Yamakura, et al., Neurosci Lett (1995) 188:187-190;
Hales, et al., Br J Pharmacol (1991) 104:619-628), I=ketamine
(Flood, et al., Anesthesiology (2000) 92:1418-1425; Hollmann,
Anesth Analg (2001) 92:1182-1191; Yamakura, et al., Anesthesiology
(2000) 92:1144-1153), J=isoflurane (Jenkins, et al., Anesthesiology
(1999) 90:484-491; Krasowski, et al., Br J Pharmacol (2000)
129:731-743; Hollmann, et al., Anesth Analg (2001) 92:1182-1191;
Yamakura, et al., Anesthesiology (2000) 93:1095-1101; Ogata, et
al., J Pharmacol Exp Ther (2006) 318:434-443), K=enflurane
(Krasowski, et al., Br J Pharmacol (2000) 129:731-743; Martin, et
al. Biochem Pharmacol (1995) 49:809-817), L=dizocilpine (Yamakura,
et al., Anesthesiology (2000) 92:1144-1153; Wong, et al., Proc Natl
Acad Sci USA (1986) 83:7104-7108), M=desflurane (Hollmann, et al.,
Anesth Analg (2001) 92:1182-1191; Nishikawa, et al., Anesthesiology
(2003) 99:678-684), N=halothane (Jenkins, et al., Anesthesiology
(1999) 90:484-491; Ogata, et al., J Pharmacol Exp Ther (2006)
318:434-443; Martin, et al., Biochem Pharmacol (1995) 49:809-817),
O=cyclopropane (Ogata, et al., J Pharmacol Exp Ther (2006)
318:434-443; Hara, et al., Anesthesiology (2002) 97:1512-1520.),
P=chloroform, 61 Q=2,6-dimethylphenol, 65 R=methoxyflurane
(Jenkins, et al., Anesthesiology (1999) 90:484-491; Krasowski, et
al., Br J Pharmacol (2000) 129:731-743; Martin, et al. Biochem
Pharmacol (1995) 49:809-817), S=diethyl ether (Krasowski, et al.,
Br J Pharmacol (2000) 129:731-743; Martin, et al. Biochem Pharmacol
(1995) 49:809-817), T=nitrous oxide (Yamakura, et al.,
Anesthesiology (2000) 93:1095-1101; Ogata, et al., J Pharmacol Exp
Ther (2006) 318:434-443), U=ethanol (Yamakura, et al.,
Anesthesiology (2000) 93:1095-1101). Most conventional and
experimental agents modulate members of 4-transmembrane ion
channels (e.g., .gamma.-aminobutyric acid Type A or GABA.sub.A
receptors, glycine receptors, and nicotinic acetylcholine
receptors) and 3-transmembrane ion channels (e.g.,
N-methyl-d-aspartate or NMDA receptors). However, agents with low
molar water solubility fail to modulate 3-tranamembrane
receptors.
[0087] FIG. 3 illustrates sample two-electrode voltage clamp
recordings from oocytes expressing either GABA.sub.A receptors
(left) or NMDA receptors (right). Black bars ( ) represent periods
of agonist exposure, and arrows () represent periods of saturated
alkane exposure. Both butane and pentane positively modulate
GABA.sub.A receptors. Butane negatively modulates NMDA receptors,
but pentane produces no effect. Hence, NMDA receptors exhibit an
alkane cut-off between butane and pentane.
[0088] FIG. 4 illustrates a summary of receptor cut-off effects as
a function of molar water solubility. For each hydrocarbon
functional group, white bars represent compounds that modulate both
GABA.sub.A and NMDA receptors, and black bars represent compounds
that modulate GABA.sub.A receptors but have no effect on NMDA
receptors at a saturating concentration. Intervening grey bars
represent solubility values for which no data exist.
[0089] FIG. 5 illustrates a summary of receptor cut-off effects as
a function of the number of drug carbon atoms. Refer to FIG. 3 for
key information. No receptor cut-off pattern is evident as a
function of the number of drug carbon atoms.
[0090] FIG. 6 illustrates a summary of receptor cut-off effects as
a function of the calculated molecular volume of each drug. Refer
to FIG. 3 for key information. No receptor cut-off pattern is
evident as a function of molecular volume.
[0091] FIG. 7 illustrates a graph of ion channel and receptor
modulation as a function of molar water solubility. Drugs modulate
channel or receptor activity over the solubility range indicated by
the white bar and do not modulate activity over the solubility
range indicated by the black bar. The grey region represents the
95% confidence interval around the solubility cut-off for 3
different hydrocarbon types (1-alcohols, n-alkanes, and dialkyl
ethers) for all channels and receptors except the NMDA receptor, on
which a total of 13 different hydrocarbon types were studied.
DETAILED DESCRIPTION
I. Introduction
[0092] The present invention is based, in part, on the surprising
discovery that the specificity of an anesthetic for an
anesthetic-sensitive receptor can be modulated (e.g., increased or
decreased) by altering the water solubility of the anesthetic.
Based on the threshold solubility cut-off values for different
families of anesthetic-sensitive receptors, anesthetics can be
designed to activate subsets of receptors with a water solubility
cut-off value that is less than the water solubility of the
anesthetic, while not activating receptors with a water solubility
cut-off value that is greater than the water solubility of the
anesthetic. Generally, anesthetics with a relatively higher water
solubility activate a larger number of anesthetic-sensitive
receptors; anesthetics with a relatively lower water solubility
activate fewer anesthetic-sensitive receptors. The present
discovery finds use in determining the specificity of a particular
anesthetic for different anesthetic-sensitive receptors, e.g., by
comparing the water solubility of the anesthetic with the threshold
solubility cut-off values of different anesthetic-sensitive
receptors. The present discovery also finds use in guiding the
rational chemical modification or derivitization of an anesthetic
to adjust its water solubility and specificity for different
anesthetic-sensitive receptors.
[0093] Some anesthetics bind with high affinity (low EC50) to
either 4-transmembrane receptors (i.e., GABA.sub.A) or
3-transmembrane receptors (i.e., NMDA), but not to members of both
receptor superfamilies. However, drugs with sufficient amphipathic
properties can modulate members of both receptor superfamilies;
this is true not only for ketamine and propofol, but for many
conventional and experimental anesthetics (FIG. 2). Based the
information in FIG. 2, sufficient water solubility appears
sufficient to allow modulation of phylogenetically unrelated
receptor superfamilies. Further, FIG. 2 would suggest that
compounds with a molar solubility less than approximately 1 mM
exhibit receptor superfamily specificity, but compounds with
greater molar aqueous solubility can modulate 3- and
4-transmembrane receptors, if applied in sufficient concentrations.
The importance of aqueous anesthetic concentration to mediate
low-affinity ion channel effects explains why receptor point
mutations near water cavities in proteins or near the plasma
membrane-extracellular interface can dramatically affect
sensitivity to volatile anesthetics (Lobo, et al.,
Neuropharmacology (2006) 50: 174-81). In addition, the anesthetic
cut-off effect with increasing hydrocarbon chain length may be due
to an insufficient molar water solubility of large hydrophobic
molecules (Katz, et al., J Theor Biol (2003) 225: 341-9). In
effect, this may not be a size cut-off, but a solubility
cut-off.
[0094] Anesthetics do not distribute equally throughout the lipid
bilayer. Halothane shows a preference for the phospholipid
headgroup interface (Vemparala, et al., Biophys J (2006) 91:
2815-25). Xenon atoms prefer regions at the lipid-water interface
and the central region of the bilayer (Stimson, et al., Cell Mol
Biol Lett (2005) 10: 563-9). The anesthetics cyclopropane, nitrous
oxide, desflurane, isoflurane, and 1,1,2-trifluoroethane (TFE) all
preferentially concentrate at the interface between water and
hexane (Pohorille et al., Toxicol Lett (1998) 100-101: 421-30).
However, perfluoroethane, a compound structurally similar to TFE,
does not exhibit an hydrophilic-hydrophobic interfacial maxima, and
it is both poorly soluble in water and a nonimmobilizer (Pohorille,
supra). It has been hypothesized that accumulation of amphipathic
anesthetics at the lipid-water interface may decrease surface
tension (Wustneck, et al., Langmuir (2007) 23: 1815-23) and reduce
the lateral pressure profile of the membrane phospholipids (Terama,
et al., J Phys Chem B (2008) 112: 4131-9). This could alter the
hydration status of membrane proteins (Ho, et al., Biophys J (1992)
63: 897-902), and thus alter conduction through ion channels. It is
possible that the "anesthetic sensitivity" of certain channels may
simply be a marker of receptors that are subject to modulation by
interfacial hydrophilic interactions.
[0095] However, there is no reason to presume that the same number
of hydrophilic or hydrophobic anesthetic interactions should be
identical for dissimilar ion channels. The 2-transmembrane (e.g.,
P2X, P2Z receptors), 3-transmembrane (e.g., AMPA, kainite, and NMDA
receptors), 4-transmembrane (nACh, 5-HT.sub.3, GABA.sub.A,
GABA.sub.C, and glycine receptors), and 7-transmembrane (G-protein
coupled receptors) superfamilies are phylogenetically unrelated
(Foreman J C, Johansen T: Textbook of Receptor Pharmacology, 2nd
Edition. Boca Raton, CRC Press, 2003). Hence, it seems likely that
the number of anesthetic molecules at the lipid water interface
necessary to modulate a receptor should be different for members of
different superfamilies, but more similar for channels within the
same superfamily since these share greater sequence homology.
[0096] If non-specific interactions of anesthetics at the
lipid-water interface are important for low-affinity and
promiscuous ion channel modulations, then at least two predictions
can be made.
[0097] First, sufficient water solubility should be important for
interfacial interactions, and thus any amphipathic molecule with
sufficient water solubility should be able to modulate
anesthetic-sensitive channels. This statement is supported by
numerous studies that show GABA.sub.A, glycine, NMDA, two-pore
domain potassium channels, and other anesthetic-sensitive channels
can be modulated by conventional and nonconventional anesthetics,
including carbon dioxide, ammonia, ketone bodies, and detergents
(Yang, et al, Anesth Analg (2008) 107: 868-74; Yang, et al., Anesth
Analg (2008) 106: 838-45; Eger, et al., Anesth Analg (2006) 102:
1397-406; Solt, et al., Anesth Analg (2006) 102: 1407-11;
Krasowski, et al., J Pharmacol Exp Ther (2001) 297: 338-51;
Brosnan, et al., Anesth Analg (2007) 104: 1430-3; Brosnan, et al.,
Br J Anaesth (2008) 101: 673-9; Mohammadi, et al., Eur J Pharmacol
(2001) 421: 85-91; Anderson, et al., J Med Chem (1997) 40: 1668-81;
Brosnan, et al., Anesth Analg (2006) 103: 86-91). 87-96). Moreover,
receptor mutations that decrease ion channel sensitivity to
conventional anesthetics can also decrease sensitivity to
nonconventional ones as well (Yang, et al., Anesth Analg (2008)
106: 838-45), suggesting these disparate compounds all share a
common nonspecific mechanism for interacting with unrelated ion
channels.
[0098] Second, the number of non-specific interfacial interactions
should be different between non-homologous channels. Hence, a prime
determinant of the cut-off effect for ion channel modulation should
be the water solubility of a drug, and this threshold solubility
cut-off concentration should differ between ion channels from
unrelated superfamilies (e.g., 3-vs. 4-transmembrane receptors).
Preliminary data supports this contention (FIG. 9). In these
studies, whole cell currents of oocytes expressing either
GABA.sub.A (human .alpha..sub.1.beta..sub.2.gamma..sub.2s)
receptors or NMDA (human NR1/rat NR2A) receptors were measured in
the presence and absence of saturated hydrocarbons with differing
functional groups. For a given homologous hydrocarbon series (with
an identical functional group), the agent solubility was varied by
increasing the hydrocarbon chain length at the .OMEGA.-position.
For example, the alkane series consisted of n-butane, n-pentane,
and n-hexane; the alcohol series consisted of 1-decanol and
1-dodecanol; the amines consisted of 1-octadecamine and
1-eicosanamine; the ethers consisted of dipentylether and
dihexylether; etc. All compounds studied were positive modulators
(>10% increase over baseline) of GABA.sub.A receptors, but only
compounds with a molar water solubility greater than approximately
1 mM were also able to modulate NMDA receptors (>10% decrease
from baseline), as shown in FIG. 9. Hence, water solubility
correlated with specificity for GABA.sub.A versus NMDA receptors.
This correlation is remarkably good since solubility values are
calculated--not measured--for compounds in unbuffered pure water
instead of the polyionic buffered solutions in which whole cell
currents were actually measured. Although increasing chain length
increases molecular volume, the specificity cut-off was not
associated with any particular hydrocarbon chain length. In
addition, increasing chain length also changes the activity of a
hydrocarbon in solution; but there was no correlation between
saturated vapor pressure and the receptor specificity cut-off.
[0099] Inhaled anesthetics enjoy widespread clinical use in general
anesthesia in animals and humans, even though these drugs pose
patient risks in terms of cardiovascular and respiratory
depression. Continued drug development is important to improving
anesthetic safety. However, all volatile anesthetics in clinical
use were developed in the 1970s or before (Terrell, Anesthesiology
(2008) 108: 531-3).
[0100] Creating newer and safer anesthetics requires knowledge of
properties that predict which receptors or receptor superfamilies
are likely to be modulated (Solt, et al., Curr Opin Anaesthesiol
2007; 20: 300-6). Data are provided herein that demonstrate a
threshold solubility related to NMDA versus GABA.sub.A receptor
specificity; analogous threshold solubility-specificity "cut-off"
values exist for other receptors as well. This is important,
because actions at various receptors and ion channels determine the
pharmacologic profile of a drug. An inhaled agent that selectively
acts on NMDA receptors can offer increased analgesia and autonomic
quiescence, as do other injectable NMDA antagonists (Cahusac, et
al., Neuropharmacology (1984) 23: 719-24; Bovill, et al., Br J
Anaesth (1971) 43: 496-9; Sanders, Br Med Bull (2004) 71: 115-35;
France, et al., J Pharmacol Exp Ther (1989) 250: 197-201; Janig, et
al., J Auton Nerv Syst (1980) 2: 1-14; and Ness, et al., Brain Res
1988; 450: 153-69). Drugs that act predominantly through certain
GABA receptors can offer excellent amnesia (Clark, et al., Arch
Neurol (1979) 36: 296-300; Bonin, et al., Pharmacol Biochem Behav
(2008) 90: 105-12; Cheng, et al., J Neurosci 2006; 26: 3713-20;
Sonner, et al., Mol Pharmacol (2005) 68: 61-8; Vanini, et al.,
Anesthesiology (2008) 109: 978-88), but may also contribute to
significant respiratory depression (Harrison, et al., Br J
Pharmacol 1985; 84: 381-91; Hedner, et al., J Neural Transm (1980)
49: 179-86; Yamada, et al., Brain Res 1982; 248: 71-8; Taveira da
Silva, et al., J Appl Physiol (1987) 62: 2264-72; Delpierre, et
al., Neurosci Lett (1997) 226: 83-6; Li, et al., J Physiol (2006)
577: 307-18; Yang, J Appl Physiol (2007) 102: 350-7). Other cut-off
values may exist for receptors that cause negative inotropy and
vasodilation, leading to cardiovascular instability in anesthetized
patients.
[0101] Knowledge of threshold cut-off values, and the means to
easily predict them through calculated estimates of a physical
property facilitates the rational design of new agents with an
improved safety profile. For example, a good analgesic with poor
immobilizing effects can be turned into a good general anesthetic
by increasing the water solubility of the agent, such as by
addition of an alcohol group or halogen, or by removal of long
aliphatic chains that are not involved with high-affinity binding
interactions. Conversely, a good immobilizer could be altered to
reduce water solubility in order eliminate certain side effects
caused by receptor modulation above that cut-off value. It is also
possible to alter activity at high affinity sites to make drugs
less potent, thereby increasing the drug ED50 and adding
potentially desirable pharmacodynamic effects from low-affinity
sites at these higher concentrations.
[0102] The discovery of threshold solubility-specificity cut-off
values allows one to make predictions regarding anesthetic
mechanisms. For example, since receptors with the same superfamily
share sequence homology, their solubility cut-off values should be
more similar to each other than receptors from different
superfamilies.
II. Compounds for Effecting Anesthesia
[0103] a. Properties of the Present Inhalational Anesthetics
[0104] Using the water solubility threshold values to predict the
efficacy and pharmacological activity of candidate compounds on
anesthetic-sensitive receptors, compounds for effecting anesthesia
via delivery through the respiratory passages have been identified.
Some of the compounds potentiate GABA.sub.A receptors without
inhibiting NMDA receptors. Candidate compounds are selected based
on their molar water solubility, vapor pressure, saline-gas
partition coefficient, carbon-to-halogen ratio, odor (or lack
thereof), stability, e.g., in formulations for inhalational or
pulmonary delivery, pharmacological activity on different
anesthetic-sensitive receptors, and toxicity.
[0105] i. Molar Water Solubility and Channel Cut-Off Values
[0106] Inhaled agents produce anesthesia via a summation of ion
channel and cell membrane receptor effects that serve to decrease
neuronal excitability within the central nervous system. Anesthetic
efficacy at specific ion channels and cell membrane receptors is
predicted by molar water solubility. Hydrocarbons that have a molar
water solubility greater than approximately 1.1 mM will modulate
NMDA receptors whereas less soluble anesthetics will generally not,
although there is small variability about this cut-off number with
alcohols continuing to modulate NMDA receptors at slightly lower
solubility values and ethers exhibiting a cut-off effect at
slightly higher solubility values. Conversely, inhaled hydrocarbons
that cannot potentiate GABA.sub.A receptors are not anesthetics.
The water solubility cut-off for GABA.sub.A receptor modulation is
around 0.068 mM, but current data from our laboratory shows a 95%
confidence interval that extends from 0.3 mM to 0.016. These
GABA.sub.A solubility cut-off values provide an absolute molar
water solubility lower-limit for rapid database screening of
potential anesthetic candidates. Inhaled agents less soluble than
0.068 mM are unlikely to exhibit an anesthetic effect. Non-gaseous
volatile compounds more soluble than 100 mM are unlikely to have
desirable pharmacokinetic properties, and this value serves as an
upper solubility limit for database screening.
[0107] ii. Vapor Pressure
[0108] Inhaled anesthetics are administered via the respiratory
system and thus need a sufficiently high vapor pressure to
facilitate rapid agent delivery to a patient. The vapor pressure
also must exceed anesthetic potency (a function of water and lipid
solubility) for the agent to be delivered via inhalation at 1
atmosphere pressure. For database screening, we selected a minimum
vapor pressure of 0.1 atmospheres (76 mmHg) at 25.degree. C.
[0109] iii. Saline-Gas Partition Coefficient
[0110] Inhaled anesthetics with low Ostwald saline-gas partition
coefficients exhibit desirable and rapid washin and washout
kinetics. These values can be estimated using previously published
QSPR correlations, or by identifying within a chemical family those
compounds that exhibit high vapor pressure and low aqueous
solubility which together suggest a low Ostwald saline-gas
partition coefficient. Compounds should have a saline-gas partition
coefficient .ltoreq.0.8 at 37.degree. C.
[0111] iv. Carbon-to-Halogen Ratio
[0112] Modern anesthetics must be non-flammable in order to be
clinically useful. Halogenation reduces flammability. Compounds for
which the number of hydrogen atoms did not exceed the number of
carbon atoms are preferred.
[0113] v. Parent Compound Properties
[0114] 1. Odor
[0115] Malodorous compounds will not be tolerated by patients or
perioperative personnel. Compounds containing thiols or sulfide
linkages and primary and secondary amine compounds have unpleasant
odors, and so volatile compounds containing these groups were
excluded from screening.
[0116] 2. Stability
[0117] Divalent bases (and sometimes monovalent bases) are used for
CO.sub.2 absorption in anesthetic circuits; clinically-useful
agents must therefore be stable in the presence of strong bases.
Compounds containing aldehyde, ketone, or carboxillic acid groups
were unstable in soda lime are not preferred. Anesthetics should
also be resistant to hydrolysis and redox reactions in vivo.
Compounds with ester linkages can be thermally unstable or
hydrolysed by plasma and tissue cholinesterases; and those
compounds resistant to hydrolysis may likely cause undesirable
inhibition of these enzymes (which are essential for metabolism of
other drugs). Therefore, compounds with ester linkages are not
preferred. Anesthetics with non-aromatic unsaturated carbon
linkages have been used historically (fluoroxene, isopropenyl vinyl
ether, trichloroethylene, vinethylene, ethylene) and shown to
undergo extensive metabolism that for some agents was associated
with toxicity. Agents containing double or triple carbon bonds are
not preferred.
[0118] 3. Anesthetic-Sensitive Channel and Receptor Effects
[0119] Clinically-relevant anesthetics should inhibit excitatory
ion channels and cell receptors and potentiate inhibitory ion
channels and cell receptors. However, tests with unhalogenated
compounds containing tertiary amines (4-methylmorpholine,
N-methylpiperadine) caused direct activation of NMDA receptors
which would be expected to antagonize anesthetic effects and
potentially cause neuronal injury at high concentrations.
Accordingly, compounds containing tertiary amines are not
preferred.
[0120] 4. In Vitro and In Vivo Toxicity
[0121] Some parent structures (such as pyrrolidine) caused
cytotoxicity during oocyte electrophysiology studies. These
compounds are not preferred. Other structures previously known to
be highly toxic to animals or humans (such as silanes and boranes)
are not preferred.
[0122] b. Illustrative Anesthetics
[0123] Illustrative anesthetic compounds having the foregoing
criteria include without limitation halogenated alcohol
derivatives, halogenated diether (polyether) derivatives,
halogenated dioxane derivatives, halogenated dioxolane derivatives,
halogenated cyclopentane derivatives, halogenated cyclohexane
derivatives, halogenated tetrahydrofuran derivatives, and
halogenated tetrahydropyran derivatives. The compounds can be
formulated for delivery to a subject via the respiratory pathways,
e.g., for inhalational or pulmonary delivery.
[0124] The compounds described herein may form salts with acids,
and such salts are included in the present invention. In one
embodiment, the salts are pharmaceutically acceptable salts. The
term "salts" embraces addition salts of free acids that are useful
within the methods of the invention. The term "pharmaceutically
acceptable salt" refers to salts that possess toxicity profiles
within a range that affords utility in pharmaceutical applications.
Pharmaceutically unacceptable salts may nonetheless possess
properties such as high crystallinity, which have utility in the
practice of the present invention, such as for example utility in
process of synthesis, purification or formulation of compounds
useful within the methods of the invention.
[0125] Suitable pharmaceutically acceptable acid addition salts may
be prepared from an inorganic acid or from an organic acid.
Examples of inorganic acids include sulfate, hydrogen sulfate,
hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric,
and phosphoric acids (including hydrogen phosphate and dihydrogen
phosphate), Appropriate organic acids may be selected from
aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,
carboxylic and sulfonic classes of organic acids, examples of which
include formic, acetic, propionic, succinic, glycolic, gluconic,
lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
trifluoromethanesulfonic, 2-hydroxyethanesulfonic,
p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,
alginic, .beta.-hydroxybutyric, salicylic, galactaric and
galacturonic acid.
[0126] Suitable pharmaceutically acceptable base addition salts of
compounds of the invention include, for example, metallic salts
including alkali metal, alkaline earth metal and transition metal
salts such as, for example, calcium, magnesium, potassium, sodium
and zinc salts, pharmaceutically acceptable base addition salts
also include organic salts made from basic amines such as, for
example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared from the corresponding
compound by reacting, for example, the appropriate acid or base
with the compound.
[0127] Some of the compounds set forth herein include chiral
centers. Chiral centers generally refer to a carbon atom that is
attached to four unique substituents. With respect to these
chiral-center containing compounds, the present invention provides
for methods that include the use of, and administration of, these
chiral-center containing compounds as either pure entantiomers, as
mixtures of enantiomers, as well as mixtures of diastereoisomers or
as a purified diastereomer. In some embodiments, the R
configuration of a particular enantiomer is preferred for a
particular method. In yet other embodiments, the S configuration of
a particular enantiomer is preferred for a particular method. The
present invention includes methods of administering racemic
mixtures of compounds having chiral centers. The present invention
includes methods of administering one particular stereoisomer of a
compound. In certain embodiments, a particular ratio of one
enantiomer to another enantiomer is preferred for use with a method
described herein. In other embodiments, a particular ratio of one
diastereomer to other diastereomers is preferred for use with a
method described herein.
[0128] i. Halogenated Alcohol Derivatives
[0129] Illustrative halogenated alcohol derivatives include without
limitation a compound or a mixture of compounds of Formula I:
##STR00008## [0130] wherein: [0131] n is 0-4, [0132] R.sup.1 is H;
[0133] R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently
are selected from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and
C.sub.2X.sub.5; and [0134] wherein X is a halogen, the compound
having vapor pressure of at least 0.1 atmospheres (76 mmHg) at
25.degree. C., and the number of hydrogen atoms in Formula I do not
exceed the number of carbon atoms, thereby inducing anesthesia in
the subject. In various embodiments, X is a halogen selected from
the group consisting of F, Cl, Br and I. In some embodiments, X is
F. In some embodiments, R.sup.1 is selected from H, CH.sub.FOH,
CHFOH and CF.sub.2OH, CHClOH, CCl.sub.2OH and CFClOH. In some
embodiments, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F.
[0135] In some embodiments, the halogenated alcohol derivatives are
selected from the group consisting of:
[0136] a) Methanol,
1-fluoro-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]-(CAS
#1351959-82-4);
[0137] b) 1-Butanol,
4,4,4-trifluoro-3,3-bis(trifluoromethyl)-(CAS#14115-49-2);
[0138] c) 1-Butanol,
1,1,2,2,3,3,4,4,4-nonafluoro-(CAS#3056-01-7);
[0139] d) 1-Butanol,
2,2,3,4,4,4-hexafluoro-3-(trifluoromethyl)-(CAS#782390-93-6);
[0140] e) 1-Butanol,
3,4,4,4-tetrafluoro-3-(trifluoromethyl)-(CAS#90999-87-4);
[0141] f) 1-Pentanol, 1,1,4,4,5,5,5-heptafluoro-(CAS#313503-66-1);
and
[0142] g) 1-Pentanol,
1,1,2,2,3,3,4,4,5,5,5-undecafluoro-(CAS#57911-98-5).
[0143] In some other embodiments, the halogenated alcohol
derivatives are selected from the group consisting of: [0144] a)
2-Pentanol,
1,1,1,3,3,5,5,5-octafluoro-2-(trifluoromethyl)-(CAS#144475-50-3);
[0145] b) 2-Pentanol,
1,1,1,3,4,5,5,5-octafluoro-4-(trifluoromethyl)-(2R,3S)-(CAS#126529-27-9);
[0146] c) 2-Pentanol, 1,1,1,3,4,4,5,5,5-nonafluoro-,
(2R,3S)-rel-(CAS#126529-24-6); [0147] d) 2-Pentanol,
1,1,1,3,4,5,5,5-octafluoro-4-(trifluoromethyl)-(2R,3R)-(CAS#126529-17-7);
[0148] e) 2-Pentanol, 1,1,1,3,4,4,5,5,5-nonafluoro-,
(2R,3R)-rel-(CAS#126529-14-4); [0149] f) 1-Butanol,
1,1,2,2,3,3,4,4-octafluoro-(CAS#119420-27-8); [0150] g) 1-Butanol,
2,3,3,4,4,4-hexafluoro-2-(trifluoromethyl)-(CAS#111736-92-6);
[0151] h) 2-Pentanol, 1,1,1,3,3,4,5,5,5-nonafluoro-, (R*,S*)-(9CI)
(CAS#99390-96-2); [0152] i) 2-Pentanol,
1,1,1,3,3,4,5,5,5-nonafluoro-, (R*,R*)-(9CI) (CAS#99390-90-6);
[0153] j) 2-Pentanol,
1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-(CAS#67728-22-7);
[0154] k) 1-Pentanol,
1,1,2,2,3,3,4,4,5,5,5-undecafluoro-(CAS#57911-98-5); [0155] l)
2-Pentanol, 1,1,1,3,3,4,4,5,5,5-decafluoro-(CAS#377-53-7); [0156]
m) 1-Pentanol, 2,2,3,4,4,5,5,5-octafluoro-(CAS#357-35-7); [0157] n)
1-Butanol,
2,3,4,4,4-pentafluoro-2-(trifluoromethyl)-(CAS#357-14-2); [0158] o)
1-Pentanol, 2,2,3,3,4,4,5,5,5-nonafluoro (CAS#355-28-2); [0159] p)
1-Butanol, 2,3,4,4,4-pentafluoro-2-(trifluoromethyl)-,(R*,S*)-(9CI)
(CAS#180068-23-9); [0160] q) 1-Butanol,
2,3,4,4,4-pentafluoro-2-(trifluoromethyl)-(R*,R*)-(9CI)
(CAS#180068-22-8); [0161] r) 2-Butanol,
1,1,1,3,3-pentafluoro-2-(trifluoromethyl)-(CAS#144444-16-6); [0162]
s) 2-Butanol, 1,1,1,3,3,4,4,4-octafluoro (CAS#127256-73-9); [0163]
t) 1-Butanol,
2,2,3,4,4,4-hexafluoro-3-(trifluoromethyl)-(CAS#782390-93-6);
[0164] u) 2-Propanol,
1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-(CAS#2378-02-01); [0165]
v) 1-Hexanol, 1,1,2,2,3,3,4,4,5,5-decafluoro (CAS#1118030-44-6);
[0166] w) 1-Hexanol,
1,1,2,2,3,3,4,4,5,5,6,6-dodecafluoro-(CAS#119420-28-9); [0167] x)
1-Hexanol, 1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluoro-(CAS#7057-81-0);
[0168] y) 1-Hexanol, 3,3,4,4,5,5,6,6,6-nonafluoro-(CAS#2043-47-2);
[0169] z) 1-Hexanol,
2,2,3,3,4,4,5,5,6,6,6-undecafluoro-(CAS#423-46-1); [0170] aa)
1-Hexanol, 2,2,3,4,4,5,5,6,6,6-decafluoro-(CAS#356-25-2); [0171]
ab) 1-Heptanol,
3,3,4,4,5,5,6,6,7,7,7-undecafluoro-(CAS#185689-57-0); [0172] ac)
1-Hexanol,
2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)-(CAS#849819-50-7);
[0173] ad) 1-Hexanol,
2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)-(CAS#89076-11-9);
[0174] ae) 1-Hexanol,
2,2,3,4,4,6,6,6-octafluoro-3,5,5-tris(trifluoromethyl)-(CAS#232267-34-4);
[0175] af) 1-Hexanol,
2,2,3,4,4,5,6,6,6-nonafluoro-3-(trifluoromethyl)-(CAS#402592-21-6);
[0176] ag) 1-Hexanol,
4,5,5,6,6,6-hexafluoro-4-(trifluoromethyl)-(CAS#239463-96-8); and
[0177] ah) 1-Hexanol,
4,4,5,5,6,6,6-heptafluoro-3,3-bis(trifluoromethyl)-(CAS#161261-12-7).
[0178] In some embodiments, the above-described halogenated alcohol
derivatives are useful as inhaled sedatives, also as inhaled
tranquilizers, also as inhaled analgesics, and also as inhaled
hypnotics. In some embodiments, the halogenated alcohol derivatives
set forth herein are useful as inhaled sedatives. In some
embodiments, the halogenated alcohol derivatives set forth herein
are useful as inhaled tranquilizers. In some embodiments, the
halogenated alcohol derivatives set forth herein are useful as
inhaled analgesics. In some embodiments, the halogenated alcohol
derivatives set forth herein are useful as inhaled hypnotics. In
some embodiments, the halogenated alcohol derivatives set forth
herein are useful as tranquilizers. In some embodiments, the
halogenated alcohol derivatives set forth herein are useful as
analgesics. In some embodiments, the halogenated alcohol
derivatives set forth herein are useful as hypnotics.
[0179] In some specific embodiments, the halogenated alcohol
derivative is selected from 1-Hexanol,
2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)-(CAS#89076-11-9).
1-Hexanol, 2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)--was
observed to be useful as a GABA-A receptor agonist and a weak NMDA
receptor antagonist at saturating aqueous phase concentrations. The
present invention includes methods of administering 1-Hexanol,
2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)--in order to
induce sedative or hypnotic states in a subject or patient.
[0180] ii. Halogenated Diether (Polyether) Derivatives
[0181] Illustrative halogenated diether (polyether derivatives)
include without limitation a compound or a mixture of compounds of
Formula II:
##STR00009## [0182] wherein: [0183] n is 1-3, [0184] R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X and C.sub.2X.sub.5; and [0185] wherein X is a halogen,
the compound having vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms in Formula
II do not exceed the number of carbon atoms, thereby inducing
anesthesia in the subject. In various embodiments, X is a halogen
selected from the group consisting of F, Cl, Br and I. In some
embodiments, X is F. In some embodiments, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F.
[0186] In some embodiments, the halogenated diether (polyether
derivatives) are selected from the group consisting of:
[0187] a) Ethane,
1,1,2-trifluoro-1,2-bis(trifluoromethoxy)-(CAS#362631-92-3);
[0188] b) Ethane,
1,1,1,2-tetrafluoro-2,2-bis(trifluoromethoxy)-(CAS#115395-39-6);
[0189] c) Ethane,
1-(difluoromethoxy)-1,1,2,2-tetrafluoro-2-(trifluoromethoxy)-(CAS#40891-9-
8-3);
[0190] d) Ethane,
1,1,2,2-tetrafluoro-1,2-bis(trifluoromethoxy)-(CAS#378-11-0);
[0191] e) Ethane,
1,2-difluoro-1,2-bis(trifluoromethoxy)-(CAS#362631-95-6); Ethane,
1,2-bis(trifluoromethoxy)-(CAS#1683-90-5);
[0192] g) Propane,
1,1,3,3-tetrafluoro-1,3-bis(trifluoromethoxy)-(CAS#870715-97-2);
[0193] h) Propane,
2,2-difluoro-1,3-bis(trifluoromethoxy)-(CAS#156833-18-0);
[0194] i) Propane,
1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethoxy)-(CAS#133640-19-4;
[0195] j) Propane,
1,1,1,3,3,3-hexafluoro-2-(fluoromethoxymethoxy)-(CAS#124992-92-3);
and
[0196] k) Propane,
1,1,1,2,3,3-hexafluoro-3-methoxy-2-(trifluoromethoxy)-(CAS#104159-55-9).
[0197] iii. Halogenated Dioxane Derivatives
[0198] Illustrative halogenated dioxane derivatives include without
limitation a compound or a mixture of compounds of Formula III:
##STR00010## [0199] wherein: [0200] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are
selected from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and
C.sub.2X.sub.5; and [0201] wherein X is a halogen, the compound has
a vapor pressure of at least 0.1 atmospheres (76 mmHg) at
25.degree. C., and the number of hydrogen atoms of Formula III do
not exceed the number of carbon atoms, thereby inducing anesthesia
in the subject. In various embodiments, X is a halogen selected
from the group consisting of F, Cl, Br and I. In some embodiments,
X is F. In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are selected
from H, F, Cl, Br, I, CF.sub.3, CHF.sub.2, CH.sub.2F,
C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, C.sub.2Cl.sub.5,
CCl.sub.2F, CClF.sub.2, CHClF, C.sub.2ClF.sub.4,
C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2, and
C.sub.2Cl.sub.4F.
[0202] In some embodiments, the halogenated dioxane derivatives are
selected from the group consisting of:
[0203] a) 1,4-Dioxane,
2,2,3,3,5,6-hexafluoro-(CAS#362631-99-0);
[0204] b) 1,4-Dioxane,
2,3-dichloro-2,3,5,5,6,6-hexafluoro-(CAS#135871-00-0);
[0205] c) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-,
trans-(9CI) (CAS#56625-45-7);
[0206] d) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-,
cis-(9CI) (CAS#56625-44-6);
[0207] e) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro-(CAS#56269-26-2);
[0208] f) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-(CAS#56269-25-1);
[0209] g) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, trans-(9CI)
(CAS#34206-83-2);
[0210] h) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-, cis-(9CI)
(CAS#34181-52-7);
[0211] i) p-Dioxane, 2,2,3,5,5,6-hexafluoro-, trans-(8CI)
(CAS#34181-51-6);
[0212] j) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro-, cis-(9CI)
(CAS#34181-50-5);
[0213] k) p-Dioxane, 2,2,3,5,6,6-hexafluoro-, trans-(8CI)
(CAS#34181-49-2);
[0214] l) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-,
(5R,6S)-rel-(CAS#34181-48-1);
[0215] m) 1,4-Dioxane, 2,2,3,3,5,5,6-heptafluoro-(CAS#34118-18-8);
and
[0216] n) 1,4-Dioxane,
2,2,3,3,5,5,6,6-octafluoro-(CAS#32981-22-9).
[0217] iv. Halogenated Dioxolane Derivatives
[0218] Illustrative halogenated dioxolane derivatives include
without limitation a compound or a mixture of compounds of Formula
IV:
##STR00011## [0219] wherein: [0220] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 independently are selected from H, X,
CX.sub.3, CHX.sub.2, CH.sub.2X and C.sub.2X.sub.5; and [0221]
wherein X is a halogen, the compound has a vapor pressure of at
least 0.1 atmospheres (76 mmHg) at 25.degree. C., and the number of
hydrogen atoms of Formula IV do not exceed the number of carbon
atoms, thereby inducing anesthesia in the subject. In various
embodiments, X is a halogen selected from the group consisting of
F, Cl, Br and I. In some embodiments, X is F. In some embodiments,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently are selected from H, F, CI, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F.
[0222] In some embodiments, the halogenated dioxolane derivatives
are selected from the group consisting of:
[0223] a) 1,3-Dioxolane,
2,4,4,5-tetrafluoro-5-(trifluoromethyl)-(CAS#344303-08-8);
[0224] b) 1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-(CAS#344303-05-5);
[0225] c) 1,3-Dioxolane,
4,4,5,5-tetrafluoro-2-(trifluoromethyl)-(CAS#269716-57-6);
[0226] d) 1,3-Dioxolane,
4-chloro-2,2,4-trifluoro-5-(trifluoromethyl)-(CAS#238754-29-5);
[0227] e) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-,
trans-(9CI) (CAS #162970-78-7);
[0228] f) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-,
cis-(9CI) (CAS#162970-76-5);
[0229] g) 1,3-Dioxolane,
4-chloro-2,2,4,5,5-pentafluoro-(CAS#139139-68-7);
[0230] h) 1,3-Dioxolane,
4,5-dichloro-2,2,4,5-tetrafluoro-(CAS#87075-00-1);
[0231] i) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-,
trans-(9CI) (CAS#85036-66-4);
[0232] j) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-,
cis-(9CI) (CAS#85036-65-3);
[0233] k) 1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-, trans-(9CI)
(CAS#85036-60-8);
[0234] l) 1,3-Dioxolane,
2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#85036-57-3);
[0235] m) 1,3-Dioxolane,
2,2-dichloro-4,4,5,5-tetrafluoro-(CAS#85036-55-1);
[0236] n) 1,3-Dioxolane,
4,4,5-trifluoro-5-(trifluoromethyl)-(CAS#76492-99-4);
[0237] o) 1,3-Dioxolane,
4,4-difluoro-2,2-bis(trifluoromethyl)-(CAS#64499-86-1);
[0238] p) 1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-,
cis-(9CI) (CAS#64499-85-0);
[0239] q) 1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-,
trans-(9CI) (CAS#64499-66-7);
[0240] r) 1,3-Dioxolane,
4,4,5-trifluoro-2,2-bis(trifluoromethyl)-(CAS#64499-65-6);
[0241] s) 1,3-Dioxolane,
2,4,4,5,5-pentafluoro-2-(trifluoromethyl)-(CAS#55135-01-8);
[0242] t) 1,3-Dioxolane, 2,2,4,4,5,5-hexafluoro-(CAS#21297-65-4);
and
[0243] u) 1,3-Dioxolane,
2,2,4,4,5-pentafluoro-5-(trifluoromethyl)-(CAS#19701-22-5).
[0244] v. Halogenated Cyclopentane Derivatives
[0245] Illustrative halogenated cyclopentane derivatives include
without limitation a compound or a mixture of compounds of Formula
V:
##STR00012## [0246] wherein: [0247] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X and C.sub.2X.sub.5; and [0248] wherein X is a halogen,
the compound has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms of Formula
V do not exceed the number of carbon atoms, thereby inducing
anesthesia in the subject. In various embodiments, X is a halogen
selected from the group consisting of F, Cl, Br and I. In some
embodiments, X is F. In some embodiments, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and
R.sup.10 independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F.
[0249] In some embodiments, the halogenated cyclopentane
derivatives are selected from the group consisting of:
[0250] a) Cyclopentane,
5-chloro-1,1,2,2,3,3,4,4-octafluoro-(CAS#362014-70-8);
[0251] b) Cyclopentane,
1,1,2,2,3,4,4,5-octafluoro-(CAS#773-17-1);
[0252] c) Cyclopentane,
1,1,2,2,3,3,4,5-octafluoro-(CAS#828-35-3);
[0253] d) Cyclopentane,
1,1,2,3,3,4,5-heptafluoro-(CAS#3002-03-7);
[0254] e) Cyclopentane,
1,1,2,2,3,3,4,4-octafluoro-(CAS#149600-73-7);
[0255] f) Cyclopentane,
1,1,2,2,3,4,5-heptafluoro-(CAS#1765-23-7);
[0256] g) Cyclopentane, 1,1,2,3,4,5-hexafluoro-(CAS#699-38-7);
[0257] h) Cyclopentane,
1,1,2,2,3,3,4-heptafluoro-(CAS#15290-77-4);
[0258] i) Cyclopentane,
1,1,2,2,3,4-hexafluoro-(CAS#199989-36-1);
[0259] j) Cyclopentane, 1,1,2,2,3,3-hexafluoro-(CAS#123768-18-3);
and
[0260] k) Cyclopentane,
1,1,2,2,3-pentafluoro-(CAS#1259529-57-1).
[0261] In some embodiments, the halogenated cyclopentane
derivatives are selected from the group consisting of:
[0262] c) Cyclopentane,
1,1,2,2,3,3,4,5-octafluoro-(CAS#828-35-3);
[0263] e) Cyclopentane,
1,1,2,2,3,3,4,4-octafluoro-(CAS#149600-73-7); and
[0264] h) Cyclopentane,
1,1,2,2,3,3,4-heptafluoro-(CAS#15290-77-4).
[0265] In some embodiments, the compound administered, or used with
any of the methods set forth herein, is
1,1,2,2,3,3,4,5-octafluorocyclopentane. In certain embodiments, the
compound has the structure selected from the group consisting
of
##STR00013##
In certain embodiments, the compound administered, or used with any
of the methods set forth herein, is selected from the group
consisting of (4R,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane,
(4S,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, and
(4R,5R)-1,1,2,2,3,3,4,5-octafluorocyclopentane. Mixtures of
(4R,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane,
(4S,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, and
(4R,5R)-1,1,2,2,3,3,4,5-octafluorocyclopentane may be used with the
methods set forth herein. The present invention also includes
administering, or using with any of the methods set forth herein, a
particular stereoisomer of 1,1,2,2,3,3,4,5-octafluorocyclopentane,
e.g., (4R,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, or
(4S,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, or
(4R,5R)-1,1,2,2,3,3,4,5-octafluorocyclopentane.
[0266] In some embodiments, the compound administered, or used with
any of the methods set forth herein, is
1,1,2,2,3,3,4-heptafluorocyclopentane (CAS#15290-77-4). In certain
embodiments, the compound has the structure selected from the group
consisting of
##STR00014##
In certain embodiments, the compound administered, or used with any
of the methods set forth herein, is selected from the group
consisting of (R)-1,1,2,2,3,3,4-heptafluorocyclopentane and
(S)-1,1,2,2,3,3,4-heptafluorocyclopentane. Mixtures, e.g., racemic
mixtures, of (R)-1,1,2,2,3,3,4-heptafluorocyclopentane and
(S)-1,1,2,2,3,3,4-heptafluorocyclopentane may be used with the
methods set forth herein. The present invention also includes
administering, or using with any of the methods set forth herein, a
particular stereoisomer of 1,1,2,2,3,3,4-heptafluorocyclopentane
(CAS#15290-77-4), e.g., (R)-1,1,2,2,3,3,4-heptafluorocyclopentane
or (S)-1,1,2,2,3,3,4-heptafluorocyclopentane.
[0267] vi. Halogenated Cyclohexane Derivatives
[0268] An illustrative halogenated cyclohexane derivative includes
without limitation 1,1,2,2,3,3,4,4-octafluoro-cyclohexane
(CAS#830-15-9).
[0269] vii. Halogenated Tetrahydrofuran Derivatives
[0270] Illustrative halogenated tetrahydrofuran derivatives include
without limitation a compound or a mixture of compounds of Formula
VI:
##STR00015## [0271] wherein: [0272] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are
selected from H, X, CX.sub.3, CHX.sub.2, CH.sub.2X and
C.sub.2X.sub.5; and [0273] wherein X is a halogen, the compound has
a vapor pressure of at least 0.1 atmospheres (76 mmHg) at
25.degree. C., and the number of hydrogen atoms of Formula VI do
not exceed the number of carbon atoms, thereby inducing anesthesia
in the subject. In various embodiments, X is a halogen selected
from the group consisting of F, Cl, Br and I. In some embodiments,
X is F. In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently are selected
from H, F, Cl, Br, I, CF.sub.3, CHF.sub.2, CH.sub.2F,
C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, C.sub.2Cl.sub.5,
CCl.sub.2F, CClF.sub.2, CHClF, C.sub.2ClF.sub.4,
C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2, and
C.sub.2Cl.sub.4F.
[0274] In some embodiments, the halogenated tetrahydrofuran
derivatives are selected from the group consisting of:
[0275] a) Furan,
2,3,4,4-tetrafluorotetrahydro-2,3-bis(trifluoromethyl)-(CAS#634191-25-6);
[0276] b) Furan,
2,2,3,3,4,4,5-heptafluorotetrahydro-5-(trifluoromethyl)-(CAS#377-83-3);
[0277] c) Furan,
2,2,3,3,4,5,5-heptafluorotetrahydro-4-(trifluoromethyl)-(CAS#374-53-8);
[0278] d) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2a,.beta.3,4a)-(9CI) (CAS#133618-53-8);
[0279] e) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2a,3a,4.beta.)-(CAS#133618-52-7);
[0280] f) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2a,3.beta.,4.alpha.)-(9CI) (CAS#133618-53-8);
[0281] g) Furan,
2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,
(2.alpha.,3.alpha.,4.beta.)-(9CI) (CAS#133618-52-7);
[0282] h) Furan,
2,2,3,3,5,5-hexafluorotetrahydro-4-(trifluoromethyl)-(CAS#61340-70-3);
[0283] i) Furan,
2,3-difluorotetrahydro-2,3-bis(trifluoromethyl)-(CAS#634191-26-7);
[0284] j) Furan,
2-chloro-2,3,3,4,4,5,5-heptafluorotetrahydro-(CAS#1026470-51-8);
[0285] k) Furan,
2,2,3,3,4,4,5-heptafluorotetrahydro-5-methyl-(CAS#179017-83-5);
[0286] l) Furan,
2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-, trans-(9CI)
(CAS#133618-59-4); and
[0287] m) Furan,
2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-, cis-(9CI)
(CAS#133618-49-2).
[0288] viii. Halogenated Tetrahydropyran Derivatives
[0289] Illustrative halogenated tetrahydropyran derivatives include
without limitation a compound or a mixture of compounds of Formula
VII:
##STR00016## [0290] wherein: [0291] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10
independently are selected from H, X, CX.sub.3, CHX.sub.2,
CH.sub.2X, and C.sub.2X.sub.5; and [0292] wherein X is a halogen,
the compound has a vapor pressure of at least 0.1 atmospheres (76
mmHg) at 25.degree. C., and the number of hydrogen atoms of Formula
VII do not exceed the number of carbon atoms, thereby inducing
anesthesia in the subject. In various embodiments, X is a halogen
selected from the group consisting of F, Cl, Br and I. In some
embodiments, X is F. In some embodiments, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and
R.sup.10 independently are selected from H, F, Cl, Br, I, CF.sub.3,
CHF.sub.2, CH.sub.2F, C.sub.2F.sub.5, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, C.sub.2Cl.sub.5, CCl.sub.2F, CClF.sub.2, CHClF,
C.sub.2ClF.sub.4, C.sub.2Cl.sub.2F.sub.3, C.sub.2Cl.sub.3F.sub.2,
and C.sub.2Cl.sub.4F.
[0293] In some embodiments, the halogenated tetrahydropyran
derivatives are selected from the group consisting of:
[0294] a) 2H-Pyran, 2,2,3,3,4,5,5,6,6-nonafluorotetrahydro-4-(CAS
#71546-79-7);
[0295] b) 2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-(trifluoromethyl)-(CAS#356-47-8)-
;
[0296] c) 2H-Pyran,
2,2,3,3,4,4,5,6,6-nonafluorotetrahydro-5-(trifluoromethyl)-(CAS#61340-74--
7);
[0297] d) 2H-Pyran,
2,2,6,6-tetrafluorotetrahydro-4-(trifluoromethyl)-(CAS#657-48-7);
[0298] e) 2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-methyl-(CAS#874634-55-6);
[0299] f) Perfluorotetrahydropyran (CAS#355-79-3);
[0300] g) 2H-Pyran, 2,2,3,3,4,5,5,6-octafluorotetrahydro-,
(4R,6S)-rel-(CAS#362631-93-4); and
[0301] h) 2H-Pyran,
2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-(CAS#65601-69-6).
III. Subjects Who May Benefit
[0302] The anesthetic compounds and methods described herein find
use for inducing anesthesia in any subject in need thereof. For
example, the subject may be undergoing a surgical procedure that
requires the induction of temporary unconsciousness and/or
immobility.
[0303] The patient receiving the anesthetic may have been selected
for having or at risk of having a sensitivity or adverse reaction
to an anesthetic that activates a particular anesthetic-sensitive
receptor or subset of anesthetic-receptors. For example, the
patient may have or be at risk of having a sensitivity or adverse
reaction to an anesthetic that activates one or more of NMDA
receptors, two-pore potassium channels, voltage-gated ion channels,
GABA receptors, glycine receptors, or another anesthetic-sensitive
receptor. In such cases, the anesthetic administered to the patient
has a water solubility that is less than the solubility threshold
concentration for the receptor for which it is sought to avoid
modulating.
[0304] In various embodiments, it may be desirable to induce in the
subject amnesia and/or immobility by potentiating GABA.sub.A
receptors, but minimize or avoid inducing possible respiratory or
neurologic side-effects that may be associated with inhibition of
NMDA receptors.
IV. Formulation and Administration
[0305] a. Formulation
[0306] The invention also encompasses the use of pharmaceutical
compositions comprising a compound or a mixture of compounds (e.g.,
of Formula I, Formula II, Formula III, Formula IV, Formula V,
Formula VI, Formula VII and/or Formula VIII, as described herein),
or salts thereof, to induce anesthesia in a subject.
[0307] Such a pharmaceutical composition may consist of at least
one compound of the invention or a salt thereof, in a form suitable
for administration to a subject, or the pharmaceutical composition
may comprise at least one compound of the invention or a salt
thereof, and one or more pharmaceutically acceptable carriers, one
or more additional ingredients, or some combination of these. The
at least one compound of the invention may be present in the
pharmaceutical composition in the form of a physiologically
acceptable salt, such as in combination with a physiologically
acceptable cation or anion, as is well known in the art.
[0308] The relative amounts of the active ingredient, the
pharmaceutically acceptable carrier, and any additional ingredients
in a pharmaceutical composition of the invention will vary,
depending upon the identity, size, and condition of the subject
treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0309] As used herein, the term "pharmaceutically acceptable
carrier" means a pharmaceutically acceptable material, composition
or carrier, such as a liquid or solid filler, stabilizer,
dispersing agent, suspending agent, diluent, excipient, thickening
agent, solvent or encapsulating material, involved in carrying or
transporting a compound useful within the invention within or to
the subject such that it may perform its intended function.
Typically, such constructs are carried or transported from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation, including
the compound useful within the invention, and not injurious to the
subject. Some examples of materials that may serve as
pharmaceutically acceptable carriers include: sugars, such as
lactose, glucose and sucrose; starches, such as corn starch and
potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter and suppository waxes; oils, such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol; polyols, such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and aluminum hydroxide; surface active agents; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol; phosphate buffer solutions; and other non-toxic compatible
substances employed in pharmaceutical formulations. As used herein,
"pharmaceutically acceptable carrier" also includes any and all
coatings, antibacterial and antifungal agents, and absorption
delaying agents, and the like that are compatible with the activity
of the compound useful within the invention, and are
physiologically acceptable to the subject. Supplementary active
compounds may also be incorporated into the compositions. The
"pharmaceutically acceptable carrier" may further include a
pharmaceutically acceptable salt of the compound useful within the
invention. Other additional ingredients that may be included in the
pharmaceutical compositions used in the practice of the invention
are known in the art and described, for example in Remington: The
Science and Practice of Pharmacy (Remington: The Science &
Practice of Pharmacy), 21.sup.st Edition, 2011, Pharmaceutical
Press, and Ansel's Pharmaceutical Dosage Forms and Drug Delivery
Systems, Allen, et al., eds., 9.sup.th Edition, 2010, Lippincott
Williams & Wilkins, which are incorporated herein by
reference.
[0310] In various embodiments, the compounds are formulated for
delivery via a respiratory pathway, e.g., suitably developed for
inhalational, pulmonary, intranasal, delivery. In various
embodiments, the compound or mixture of compounds is vaporized into
or directly mixed or diluted with a carrier gas, e.g., oxygen, air,
or helium, or a mixture thereof. A preservative may be further
included in the vaporized formulations, as appropriate. Other
contemplated formulations include projected nanoparticles, and
liposomal preparations. The route(s) of administration will be
readily apparent to the skilled artisan and will depend upon any
number of factors including the type and severity of the disease
being treated, the type and age of the veterinary or human patient
being treated, and the like.
[0311] The formulations of the pharmaceutical compositions
described herein may be prepared by any method known or hereafter
developed in the art of pharmacology. In general, such preparatory
methods include the step of bringing the active ingredient into
association with a carrier or one or more other accessory
ingredients, and then, if necessary or desirable, shaping or
packaging the product into a desired single- or multi-dose
unit.
[0312] As used herein, a "unit dose" is a discrete amount of the
pharmaceutical composition comprising a predetermined amount of the
active ingredient. The amount of the active ingredient is generally
equal to the dosage of the active ingredient that would be
administered to a subject or a convenient fraction of such a dosage
such as, for example, one-half or one-third of such a dosage. The
unit dosage form may be for a single daily dose or one of multiple
daily doses (e.g., about 1 to 4 or more times per day). When
multiple daily doses are used, the unit dosage form may be the same
or different for each dose.
[0313] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for ethical administration to
humans, it will be understood by the skilled artisan that such
compositions are generally suitable for administration to animals
of all sorts. Modification of pharmaceutical compositions suitable
for administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design and
perform such modification with merely ordinary, if any,
experimentation. Subjects to which administration of the
pharmaceutical compositions of the invention is contemplated
include, but are not limited to, humans and other primates, mammals
including commercially relevant mammals including agricultural
mammals (e.g., cattle, pigs, horses, sheep), domesticated mammals
(e.g., cats, and dogs), and laboratory mammals (e.g., rats, mice,
rabbits, hamsters).
[0314] b. Administration
[0315] In some embodiments, the methods further comprise
administering the selected anesthetic (e.g., a compound or mixture
of compounds of Formula I, Formula II, Formula III, Formula IV,
Formula V, Formula VI, Formula VII and/or Formula VIII, as
described herein) to a patient. The anesthetic can be administered
by any route sufficient to achieve a desired anesthetic, amnestic,
analgesic, or sedative effect. For example, the anesthetic can be
administered intravenously, inhalationally, subcutaneously,
intramuscularly, transdermally, topically, or by any other route to
achieve an efficacious effect.
[0316] The anesthetic is administered at a dose sufficient to
achieve a desired anesthetic endpoint, for example, immobility,
amnesia, analgesia, unconsciousness or autonomic quiescence.
[0317] Administered dosages for anesthetic agents are in accordance
with dosages and scheduling regimens practiced by those of skill in
the art. General guidance for appropriate dosages of
pharmacological agents used in the present methods is provided in
Goodman and Gilman's The Pharmacological Basis of Therapeutics,
12th Edition, 2010, supra, and in a Physicians' Desk Reference
(PDR), for example, in the 65.sup.th (2011) or 66.sup.th (2012)
Eds., PDR Network, each of which is hereby incorporated herein by
reference.
[0318] The appropriate dosage of anesthetic agents will vary
according to several factors, including the chosen route of
administration, the formulation of the composition, patient
response, the severity of the condition, the subject's weight, and
the judgment of the prescribing physician. The dosage can be
increased or decreased over time, as required by an individual
patient. Usually, a patient initially is given a low dose, which is
then increased to an efficacious dosage tolerable to the
patient.
[0319] Determination of an effective amount is well within the
capability of those skilled in the art, especially in light of the
detailed disclosure provided herein. Generally, an efficacious or
effective amount of a combination of one or more anesthetic agents
is determined by first administering a low dose or small amount of
the anesthetic, and then incrementally increasing the administered
dose or dosages, adding a second or third medication as needed,
until a desired effect is observed in the treated subject with
minimal or no toxic side effects. Applicable methods for
determining an appropriate dose and dosing schedule for
administration of anesthetics are described, for example, in
Goodman and Gilman's The Pharmacological Basis of Therapeutics,
12th Edition, 2010, supra; in a Physicians' Desk Reference (PDR),
supra; in Remington: The Science and Practice of Pharmacy
(Remington: The Science & Practice of Pharmacy), 21st Edition,
2011, Pharmaceutical Press, and Ansel's Pharmaceutical Dosage Forms
and Drug Delivery Systems, Allen, et al., eds., 9th Edition, 2010,
Lippincott Williams & Wilkins; and in Martindale: The Complete
Drug Reference, Sweetman, 2005, London: Pharmaceutical Press., and
in Martindale, Martindale: The Extra Pharmacopoeia, 31st Edition.,
1996, Amer Pharmaceutical Assn, each of which are hereby
incorporated herein by reference.
[0320] Dosage amount and interval can be adjusted individually to
provide plasma levels of the active compounds which are sufficient
to maintain a desired therapeutic effect. Preferably,
therapeutically effective serum levels will be achieved by
administering a single dose, but efficacious multiple dose
schedules are included in the invention. In cases of local
administration or selective uptake, the effective local
concentration of the drug may not be related to plasma
concentration. One having skill in the art will be able to optimize
therapeutically effective local dosages without undue
experimentation.
[0321] The dosing of analog compounds can be based on the parent
compound, at least as a starting point.
[0322] In various embodiments, the compositions are delivered to
the subject via a respiratory pathway, e.g., via inhalational,
pulmonary and/or intranasal delivery. Technologies and devices for
inhalational anesthetic drug dosing are known in the art and
described, e.g., in MILLER'S ANESTHESIA, Edited by Ronald D.
Miller, et al., 2 vols, 7th ed, Philadelphia, Pa., Churchill
Livingstone/Elsevier, 2010; and Meyer, et al., Handb Exp Pharmacol.
(2008) (182):451-70. In one embodiment, the pharmaceutical
compositions useful for inducing anesthesia can be administered to
deliver a dose of between about 0.1-10.0 percent of 1 atmosphere (1
atm), e.g., 0.5-5.0 percent of 1 atm, e.g., about 1.0-3.5 of 1 atm,
e.g., about 0.1, 0.2, 0.3, 0.4. 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5,
4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0
percent of 1 atm, e.g., delivered over the period of time of
desired anesthesia. The dose used will be dependent upon the drug
potency, and the compound or mixture of compounds administered.
[0323] Detailed information about the delivery of therapeutically
active agents in the form of vapors or gases is available in the
art. The compound will typically be vaporized using a vaporizer
using a carrier gas such as oxygen, air, or helium, or a mixture
thereof, to achieve a desired drug concentration suitable for
inhalation by use of a semi-open or semi-closed anesthetic circuit,
as is known to individuals familiar with the art of anesthesia. The
compound in a gaseous form may also be directly mixed with a
carrier gas such as oxygen, air, or helium, or a mixture thereof,
to achieve a desired drug concentration suitable for inhalation by
use of a semi-open or semi-closed anesthetic circuit, as is known
to individuals familiar with the art of anesthesia. The drug may
also be administered by direct application of onto or through a
breathing mask, also termed an open circuit, as is known to
individuals familiar with the art of anesthesia. In animals, the
drug may also be administered into a closed chamber or container
containing the animal subject whereby the drug is delivered by the
respiratory tract as the animal breathes, as is known to
individuals familiar with animal anesthesia.
[0324] In some aspects of the invention, the anesthetic compound or
mixture of compounds, is dissolved or suspended in a suitable
solvent, such as water, ethanol, or saline, and administered by
nebulization. A nebulizer produces an aerosol of fine particles by
breaking a fluid into fine droplets and dispersing them into a
flowing stream of gas. Medical nebulizers are designed to convert
water or aqueous solutions or colloidal suspensions to aerosols of
fine, inhalable droplets that can enter the lungs of a patient
during inhalation and deposit on the surface of the respiratory
airways. Typical pneumatic (compressed gas) medical nebulizers
develop approximately 15 to 30 microliters of aerosol per liter of
gas in finely divided droplets with volume or mass median diameters
in the respirable range of 2 to 4 micrometers. Predominantly, water
or saline solutions are used with low solute concentrations,
typically ranging from 1.0 to 5.0 mg/mL.
[0325] Nebulizers for delivering an aerosolized solution to the
lungs are commercially available from a number of sources,
including the AERx.TM. (Aradigm Corp., Hayward, Calif.) and the
Acorn II.RTM. (Vital Signs Inc., Totowa, N.J.).
[0326] Metered dose inhalers are also known and available. Breath
actuated inhalers typically contain a pressurized propellant and
provide a metered dose automatically when the patient's inspiratory
effort either moves a mechanical lever or the detected flow rises
above a preset threshold, as detected by a hot wire anemometer.
See, for example, U.S. Pat. Nos. 3,187,748; 3,565,070; 3,814,297;
3,826,413; 4,592,348; 4,648,393; 4,803,978; and 4,896,832.
[0327] In some embodiments, the present invention provides methods
for producing analgesia in a subject, comprising administering to
the subject via the respiratory system an effective amount of a
compound or a mixture of compounds which are described herein. In
some embodiments, the analgesia includes tranquilization. In some
embodiments, the analgesia includes sedation. In some embodiments,
the analgesia includes amnesia. In some embodiments, the analgesia
includes a hypnotic state. In some embodiments, the analgesia
includes a state of insensitivity to noxious stimulation.
[0328] In some embodiments, the present invention provides methods
of producing tranquilization or sedation in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds which are
described herein. In certain embodiments, the present invention
provides methods of producing tranquilization in a subject,
comprising administering to the subject via the respiratory system
an effective amount of a compound or a mixture of compounds which
are described herein. In some other embodiments, the present
invention provides methods of producing amnesia in a subject,
comprising administering to the subject via the respiratory system
an effective amount of a compound or a mixture of compounds which
are described herein. Typically, the amount of a compound or a
mixture of compounds which are described herein that is required to
produce amnesia in a subject is larger than the amount required to
produce tranquilization in a subject. In yet other embodiments, the
present invention provides methods of producing a hypnotic state in
a subject, comprising administering to the subject via the
respiratory system an effective amount of a compound or a mixture
of compounds which are described herein. Typically, the amount of a
compound or a mixture of compounds which are described herein that
is required to produce a hypnotic state in a subject is larger than
the amount required to produce amnesia in a subject. In still other
embodiments, the present invention provides methods of producing a
state of insensitivity to noxious stimulation in a subject,
comprising administering to the subject via the respiratory system
an effective amount of a compound or a mixture of compounds which
are described herein. Typically, the amount of a compound or a
mixture of compounds which are described herein that is required to
produce a state of insensitivity to noxious stimulation in a
subject is larger than the amount required to produce a hypnotic
state in a subject.
[0329] In some embodiments, the present invention provides methods
of inducing tranquilization or sedation in a subject, comprising
administering to the subject via the respiratory system an
effective amount of a compound or a mixture of compounds which are
described herein. In certain embodiments, the present invention
provides methods of inducing tranquilization in a subject,
comprising administering to the subject via the respiratory system
an effective amount of a compound or a mixture of compounds which
are described herein. In some other embodiments, the present
invention provides methods of inducing amnesia in a subject,
comprising administering to the subject via the respiratory system
an effective amount of a compound or a mixture of compounds which
are described herein. Typically, the amount of a compound or a
mixture of compounds which are described herein that is required to
induce amnesia in a subject is larger than the amount required to
induce tranquilization in a subject. In yet other embodiments, the
present invention provides methods of inducing a hypnotic state in
a subject, comprising administering to the subject via the
respiratory system an effective amount of a compound or a mixture
of compounds which are described herein. Typically, the amount of a
compound or a mixture of compounds which are described herein that
is required to induce a hypnotic state in a subject is larger than
the amount required to induce amnesia in a subject. In still other
embodiments, the present invention provides methods of inducing a
state of insensitivity to noxious stimulation in a subject,
comprising administering to the subject via the respiratory system
an effective amount of a compound or a mixture of compounds which
are described herein. Typically, the amount of a compound or a
mixture of compounds which are described herein that is required to
induce a state of insensitivity to noxious stimulation in a subject
is larger than the amount required to induce a hypnotic state in a
subject.
[0330] The present invention includes methods of inducing a
spectrum of states of anesthesia in a subject as a function of the
administered dosage of a compound or a mixture of compounds which
are described herein. In some embodiments, the methods include
administering low dosages of a compound or a mixture of compounds
which are described herein to induce tranquilization or sedation in
a subject. In some other embodiments, the methods include
administering higher dosages than that required to induce
tranquilization of a compound or a mixture of compounds which are
described herein to induce amnesia in a subject. In yet other
embodiments, the methods include administering even higher dosages
than that required to induce amnesia in a subject of a compound or
a mixture of compounds which are described herein to induce a
hypnotic state in a subject. In still other embodiments, the
methods include administering yet even higher dosages than that
required to induce a hypnotic state in a subject of a compound or a
mixture of compounds which are described herein to induce a state
of insensitivity to noxious stimulation in a subject.
V. Methods of Determining the Specificity of an Anesthetic for an
Anesthetic Sensitive Receptor
[0331] The present invention provides methods for determining the
specificity or selective activation of an anesthetic for an
anesthetic-sensitive receptor by determining the water solubility
of the anesthetic and comparing the water solubility of the
anesthetic with a water solubility cut-off or threshold value for
the anesthetic-sensitive receptor. An anesthetic with a water
solubility that is below the water solubility cut-off or threshold
value for the anesthetic-sensitive receptor will not activate that
receptor. An anesthetic with a water solubility that is above the
water solubility cut-off or threshold value for the
anesthetic-sensitive receptor can activate that receptor.
[0332] a. Anesthetics
[0333] The anesthetic can be any compound with anesthetic
properties when administered to a patient. Generally, increasing
doses of an anesthetic causes immobility, amnesia, analgesia,
unconsciousness and autonomic quiescence in a patient. The
anesthetics are general anesthetics (e.g., systemic) and can be
inhalational or injectable.
[0334] In some embodiments, the anesthetic is an inhalational
anesthetic. For example, in some embodiments, the anesthetic is
selected from the group consisting of ethers and halogenated ethers
(including, e.g., desflurane, enflurane, halothane, isoflurane,
methoxyflurane, sevoflurane, diethyl ether, methyl propyl ether,
and analogues thereof); alkanes and halogenated alkanes (including,
e.g., halothane, chloroform, ethyl chloride, and analogues
thereof), cycloalkanes and cyclohaloalkanes (including, e.g.,
cyclopropane and analogues thereof), alkenes and haloalkenes
(including, e.g., trichloroethylene, ethylene, and analogues
thereof), alkynes and haloalkynes and their analogues, vinyl ethers
(including, e.g., ethyl vinyl ether, divinyl ether, fluoroxine, and
analogues thereof). In some embodiments, the anesthetic is selected
from the group consisting of desflurane, enflurane, halothane,
isoflurane, methoxyflurane, nitrous oxide, sevoflurane, xenon, and
analogs thereof. In some embodiments, the anesthetic is selected
from the group consisting of halogenated alcohols, halogenated
diethers, halogenated dioxanes, halogenated dioxolanes, halogenated
cyclopentanes, halogenated cyclohexanes, halogenated
tetrahydrofurans and halogenated tetrahydropyrans, as described
herein. In various embodiments, the inhalational anesthetic is a
compound or mixture of compounds of Formula I, Formula II, Formula
III, Formula IV, Formula V, Formula VI, Formula VII and/or Formula
VIII, as described herein.
[0335] In some embodiments, the anesthetic is an injectable
anesthetic or sedative drug. For example, in some embodiments, the
anesthetic is selected from the group consisting of alkyl phenols
(including, e.g., propofol and analogues thereof), imidazole
derivatives (including, e.g., etomidate, metomidate, clonidine,
detomidine, medetomidine, dexmedetomidine, and analogues thereof),
barbiturates and analogues thereof, benzodiazepines and analogues
thereof, cyclohexylamines (including, e.g., ketamine, tiletamine,
and analogues thereof), steroid anesthetics (including, e.g.,
alphaxalone and analogues thereof), opioids and opioid-like
compounds (including, e.g., natural morphine and derivatives,
codeine and derivatives, papaverine and derivatives, thebaine and
derivatives, morphinans and derivatives, diphenylpropylamines and
derivatives, benzmorphans and derivatives, phenylpiperadines and
derivatives), phenothiazines and halogenated phenothiazine
compounds and analogues thereof, buterophenones and halogenated
buterophenone compounds and analogues thereof, guaicols and
halogenated guaicols (including, e.g., eugenol and analogues
thereof), and substituted benzoates and halobenzoate derivatives
(including, e.g., tricaine and analogues thereof). In some
embodiments, the anesthetic is selected from the group consisting
of propofol, etomidate, barbiturates, benzodiazepines, ketamine,
and analogs thereof.
[0336] Anesthetic compounds are generally known in the art and are
described in, e.g., Goodman and Gilman's The Pharmacological Basis
of Therapeutics, 12th Edition, 2010, supra, and in a Physicians'
Desk Reference (PDR), for example, in the 65.sup.th (2011) or
66.sup.th (2012) Eds., PDR Network.
[0337] b. Anesthetic-Sensitive Receptors
[0338] Anesthetic-sensitive receptors are receptors and ion
channels that bind to and are activated by anesthetics.
Anesthetic-sensitive receptors include 2-, 3-, 4-, and
7-transmembrane receptor proteins. Exemplary anesthetic-sensitive
receptors include glycine receptors, GABA receptors, two-pore
domain potassium channels (K.sub.2P), voltage-gated sodium channels
(Na.sub.v), NMDA receptors, opioid receptors and subtypes of such
receptors. Anesthetic-sensitive receptors are well-known in the
art. Their sequences are well characterized.
[0339] N-methyl-D-aspartate (NMDA) receptor channels are heteromers
composed of three different subunits: NR1 (GRIN1), NR2 (GRIN2A,
GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The NR2
subunit acts as the agonist binding site for glutamate. This
receptor is the predominant excitatory neurotransmitter receptor in
the mammalian brain. NMDA receptors are reviewed, e.g., in Albensi,
Curr Pharm Des (2007) 13(31):3185-94: Paoletti and Neyton, Curr
Opin Pharmacol (2007) 7(1):39-47; Cull-Candy, et al., Curr Opin
Neurobiol (2001) 11(3):327-35. The GenBank Accession Nos. for
isoforms of human NMDA NR1 (NMDAR1, GRIN1) include
NM.sub.--000832.6.fwdarw.NP.sub.--000823.4 (NR1-1),
NM.sub.--021569.3.fwdarw.NP.sub.--067544.1 (NR1-2),
NM.sub.--007327.3.fwdarw.NP.sub.--015566.1 (NR1-3),
NM.sub.--001185090.1 NP.sub.--001172019.1 (NR1-4);
NM.sub.--001185091.1.fwdarw.NP.sub.--001172020.1 (NR1-5); the
GenBank Accession Nos. for isoforms of human NMDA NR2A (NMDAR2A,
GRIN2A) include NM.sub.--000833.3.fwdarw.NP.sub.--000824.1 (isoform
1), NM.sub.--001134407.1.fwdarw.NP.sub.--001127879.1 (isoform 1),
NM.sub.--001134408.1.fwdarw.NP.sub.--001127880.1 (isoform 2); the
GenBank Accession No. for human NMDA NR2B (NMDAR2B, GRIN2B)
includes NM.sub.--000834.3.fwdarw.NP.sub.--000825.2; the GenBank
Accession No. for human NMDA NR2C (NMDAR2C, GRIN2C) includes
NM.sub.--000835.3.fwdarw.NP.sub.--000826.2; the GenBank Accession
No. for human NMDA NR2D (NMDAR2D, GRIN2D) includes
NM.sub.--000836.2.fwdarw.NP.sub.--000827.2; the GenBank Accession
No. for human NMDA NR3A (NMDAR3A, GRIN3A) includes
NM.sub.--133445.2.fwdarw.NP.sub.--597702.2; the GenBank Accession
No. for human NMDA NR3B (NMDAR3B, GRIN3B) includes
NM.sub.--138690.1.fwdarw.NP.sub.--619635.1. NMDA receptor sequences
are also well-characterized for non-human mammals.
[0340] Gamma-aminobutyric acid (GABA)-A receptors are pentameric,
consisting of proteins from several subunit classes: alpha, beta,
gamma, delta and rho. GABA receptors are reviewed, e.g., in
Belelli, et al., J Neurosci (2009) 29(41):12757-63; and Munro, et
al., Trends Pharmacol Sci (2009) 30(9):453-9. GenBank Accession
Nos. for variants of human GABA-A receptor, alpha 1 (GABRA1)
include NM.sub.--000806.5.fwdarw.NP.sub.--000797.2 (variant 1),
NM.sub.--001127643.1.fwdarw.NP.sub.--001121115.1 (variant 2),
NM.sub.--001127644.1.fwdarw.NP.sub.--001121116.1 (variant 3),
NM.sub.--001127645.1.fwdarw.NP.sub.--001121117.1 (variant 4),
NM.sub.--001127646.1.fwdarw.NP.sub.--001121118.1 (variant 5),
NM.sub.--001127647.1.fwdarw.NP.sub.--001121119.1 (variant 6),
NM.sub.--001127648.1.fwdarw.NP.sub.--001121120.1 (variant 7).
GenBank Accession Nos. for variants of human GABA-A receptor, alpha
2 (GABRA2) include NM.sub.--000807.2.fwdarw.NP.sub.--000798.2
(variant 1), NM.sub.--001114175.1.fwdarw.NP.sub.--001107647.1
(variant 2). GenBank Accession No. for human GABA-A receptor, alpha
3 (GABRA3) includes NM.sub.--000808.3.fwdarw.NP.sub.--000799.1.
GenBank Accession Nos. for variants of human GABA-A receptor, alpha
4 (GABRA4) include NM.sub.--000809.3.fwdarw.NP.sub.--000800.2
(variant 1), NM.sub.--001204266.1.fwdarw.NP.sub.--001191195.1
(variant 2), NM.sub.--001204267.1 NP.sub.--001191196.1 (variant 3).
GenBank Accession Nos. for variants of human GABA-A receptor, alpha
5 (GABRA5) include NM.sub.--000810.3.fwdarw.NP.sub.--000801.1
(variant 1), NM.sub.--001165037.1.fwdarw.NP.sub.--001158509.1
(variant 2). GenBank Accession No. for human GABA-A receptor, alpha
6 (GABRA6) includes NM.sub.--000811.2.fwdarw.NP.sub.--000802.2.
GenBank Accession No. for human GABA-A receptor, beta 1 (GABRB1)
includes NM.sub.--000812.3.fwdarw.NP.sub.--000803.2. GenBank
Accession Nos. for variants of human GABA-A receptor, beta 2
(GABRB2) include NM.sub.--021911.2.fwdarw.NP.sub.--068711.1
(variant 1), NM.sub.--000813.2.fwdarw.NP.sub.--000804.1 (variant
2). GenBank Accession Nos. for variants of human GABA-A receptor,
beta 3 (GABRB3) include NM.sub.--000814.5.fwdarw.NP.sub.--000805.1
(variant 1), NM.sub.--021912.4.fwdarw.NP.sub.--068712.1 (variant
2), NM.sub.--001191320.1.fwdarw.NP.sub.--001178249.1 (variant 3),
NM.sub.--001191321.1.fwdarw.NP.sub.--001178250.1 (variant 4).
GenBank Accession No. for human GABA-A receptor, gamma 1 (GABRG1)
includes NM.sub.--173536.3.fwdarw.NP.sub.--775807.2. GenBank
Accession Nos. for variants of human GABA-A receptor, gamma 2
(GABRG2) include NM.sub.--198904.2.fwdarw.NP.sub.--944494.1
(variant 1), NM.sub.--000816.3.fwdarw.NP.sub.--000807.2 (variant
2), NM.sub.--198903.2.fwdarw.NP.sub.--944493.2 (variant 3). GenBank
Accession No. for human GABA-A receptor, gamma 3 (GABRG3) includes
NM.sub.--033223.4.fwdarw.NP.sub.--150092.2. GenBank Accession Nos.
for variants of human GABA-A receptor, rho 1 (GABRR1) include
NM.sub.--002042.4.fwdarw.NP.sub.--002033.2 (variant 1),
NM.sub.--001256703.1.fwdarw.NP.sub.--001243632.1 (variant 2),
NM.sub.--001256704.1.fwdarw.NP.sub.--001243633.1 (variant 3),
NM.sub.--001267582.1.fwdarw.NP.sub.--001254511.1 (variant 4).
GenBank Accession No. for human GABA-A receptor, rho 2 (GABRR2)
includes NM.sub.--002043.2.fwdarw.NP.sub.--002034.2. GenBank
Accession No. for human GABA-A receptor, rho 3 (GABRR3) includes
NM.sub.--001105580.2.fwdarw.NP.sub.--001099050.1.
[0341] Voltage-sensitive sodium channels are heteromeric complexes
consisting of a large central pore-forming glycosylated alpha
subunit, and two smaller auxiliary beta subunits. Voltage-gated
sodium channels are reviewed, e.g., in French and Zamponi, IEEE
Trans Nanobioscience (2005) 4(1):58-69; Bezanilla, IEEE Trans
Nanobioscience (2005) 4(1):34-48; Doherty and Farmer, Handb Exp
Pharmacol (2009) 194:519-61; England, Expert Opin Investig Drugs
(2008) 17(12):1849-64; and Marban, et al., J Physiol (1998)
508(3):647-57. GenBank Accession Nos. for variants of sodium
channel, voltage-gated, type I, alpha subunit (SCN1A, Nav1.1)
include NM.sub.--001165963.1.fwdarw.NP.sub.--001159435.1 (variant
1), NM.sub.--006920.4.fwdarw.NP.sub.--008851.3 (variant 2),
NM.sub.--001165964.1.fwdarw.NP.sub.--001159436.1 (variant 3),
NM.sub.--001202435.1.fwdarw.NP.sub.--001189364.1 (variant 4).
GenBank Accession Nos. for variants of sodium channel,
voltage-gated, type II, alpha subunit (SCN2A, Nav1.2) include
NM.sub.--021007.2.fwdarw.NP.sub.--066287.2 (variant 1),
NM.sub.--001040142.1.fwdarw.NP.sub.--001035232.1 (variant 2),
NM.sub.--001040143.1.fwdarw.NP.sub.--001035233.1 (variant 3).
GenBank Accession Nos. for variants of sodium channel,
voltage-gated, type III, alpha subunit (SCN3A, Nav1.3) include
NM.sub.--006922.3.fwdarw.NP.sub.--008853.3 (variant 1),
NM.sub.--001081676.1.fwdarw.NP.sub.--001075145.1 (variant 2),
NM.sub.--001081677.1.fwdarw.NP.sub.--001075146.1 (variant 3).
GenBank Accession No. for sodium channel, voltage-gated, type IV,
alpha subunit (SCN4A, Nav1.4) includes
NM.sub.--000334.4.fwdarw.NP.sub.--000325.4. GenBank Accession Nos.
for variants of sodium channel, voltage-gated, type V, alpha
subunit (SCN5A, Nav1.5) include NM.sub.--198056.2 NP.sub.--932173.1
(variant 1), NM.sub.--000335.4.fwdarw.NP.sub.--000326.2 (variant
2), NM.sub.--001099404.1.fwdarw.NP.sub.--001092874.1 (variant 3),
NM.sub.--001099405.1.fwdarw.NP.sub.--001092875.1 (variant 4),
NM.sub.--001160160.1.fwdarw.NP.sub.--001153632.1 (variant 5),
NM.sub.--001160161.1.fwdarw.NP.sub.--001153633.1 (variant 6).
GenBank Accession No. for sodium channel, voltage-gated, type VII,
alpha subunit (SCN6A, SCN7A, Nav2.1, Nav2.2) includes
NM.sub.--002976.3.fwdarw.NP.sub.--002967.2. GenBank Accession Nos.
for variants of sodium channel, voltage-gated, type VIII, alpha
subunit (SCN8A, Nav1.6) include
NM.sub.--014191.3.fwdarw.NP.sub.--055006.1 (variant 1),
NM.sub.--001177984.2.fwdarw.NP.sub.--001171455.1 (variant 2).
GenBank Accession No. for sodium channel, voltage-gated, type IX,
alpha subunit (SCN9A, Nav1.7) includes
NM.sub.--002977.3.fwdarw.NP.sub.--002968.1. GenBank Accession No.
for sodium channel, voltage-gated, type X, alpha subunit (SCN10A,
Nav1.8) includes NM.sub.--006514.2.fwdarw.NP.sub.--006505.2.
GenBank Accession No. for sodium channel, voltage-gated, type XI,
alpha subunit (SCN11A, Nav1.9) includes
NM.sub.--014139.2.fwdarw.NP.sub.--054858.2. GenBank Accession Nos.
for variants of sodium channel, voltage-gated, type I, beta subunit
(SCN1B) include NM.sub.--001037.4.fwdarw.NP.sub.--001028.1 (variant
a), NM.sub.--199037.3.fwdarw.NP.sub.--950238.1 (variant b). GenBank
Accession No. for sodium channel, voltage-gated, type II, beta
subunit (SCN2B) includes
NM.sub.--004588.4.fwdarw.NP.sub.--004579.1. GenBank Accession Nos.
for variants of sodium channel, voltage-gated, type III, beta
subunit (SCN3B) include NM.sub.--018400.3.fwdarw.NP.sub.--060870.1
(variant 1), NM.sub.--001040151.1.fwdarw.NP.sub.--001035241.1
(variant 2). GenBank Accession Nos. for variants of sodium channel,
voltage-gated, type IV, beta subunit (SCN4B) include
NM.sub.--174934.3.fwdarw.NP.sub.--777594.1 (variant 1),
NM.sub.--001142348.1.fwdarw.NP.sub.--001135820.1 (variant 2),
NM.sub.--001142349.1.fwdarw.NP.sub.--001135821.1 (variant 3).
[0342] Glycine receptors are pentamers composed of alpha and beta
subunits. Glycine receptors are reviewed, e.g., in Kuhse, et al.,
Curr Opin Neurobiol (1995) 5(3):318-23; Betz, et al., Ann NY Acad
Sci (1999) 868:667-76; Colquhoun and Sivilotti, Trends Neurosci
(2004) 27(6):337-44; and Cascio, J Biol Chem (2004)
279(19):19383-6. GenBank Accession Nos. for variants of glycine
receptor, alpha 1 (GLRA1) include
NM.sub.--001146040.1.fwdarw.NP.sub.--001139512.1 (variant 1),
NM.sub.--000171.3.fwdarw.NP.sub.--000162.2 (variant 2). GenBank
Accession Nos. for variants of glycine receptor, alpha 2 (GLRA2)
include NM.sub.--002063.3.fwdarw.NP.sub.--002054.1 (variant 1),
NM.sub.--001118885.1.fwdarw.NP.sub.--001112357.1 (variant 2),
NM.sub.--001118886.1.fwdarw.NP.sub.--001112358.1 (variant 3),
NM.sub.--001171942.1.fwdarw.NP.sub.--001165413.1 (variant 4).
GenBank Accession Nos. for variants of glycine receptor, alpha 3
(GLRA3) include NM.sub.--006529.2.fwdarw.NP.sub.--006520.2 (isoform
a), NM.sub.--001042543.1.fwdarw.NP.sub.--001036008.1 (isoform b).
GenBank Accession Nos. for variants of glycine receptor, alpha 4
(GLRA4) include NM.sub.--001024452.2.fwdarw.NP.sub.--001019623.2
(variant 1), NM.sub.--001172285.1.fwdarw.NP.sub.--001165756.1
(variant 2). GenBank Accession Nos. for variants of glycine
receptor, beta (GLRB) include
NM.sub.--000824.4.fwdarw.NP.sub.--000815.1 (variant 1),
NM.sub.--001166060.1.fwdarw.NP.sub.--001159532.1 (variant 2),
NM.sub.--001166061.1.fwdarw.NP.sub.--001159533.1 (variant 3).
[0343] Two-pore potassium channels are reviewed, e.g., in Besana,
et al., Prostaglandins Other Lipid Mediat (2005) 77(1-4):103-10;
Lesage and Lazdunski, Am J Physiol Renal Physiol (2000)
279(5):F793-801; Bayliss and Barrett, Trends Pharmacol Sci (2008)
29(11):566-75; Reyes, et al., J Biol Chem (1998) 273(47):30863-9;
and Kang and Kim, Am J Physiol Cell Physiol (2006) 291(1):C138-46.
GenBank Accession Nos. for variants of potassium channel, subfamily
K, member 2 (KCNK2, TREK1, K2p2.1) include
NM.sub.--001017424.2.fwdarw.NP.sub.--001017424.1 (variant 1),
NM.sub.--014217.3.fwdarw.NP.sub.--055032.1 (variant 2),
NM.sub.--001017425.2.fwdarw.NP.sub.--001017425.2 (variant 3).
GenBank Accession No. for potassium channel, subfamily K, member 3
(KCNK3, TASK; TBAK1; K2p3.1) includes
NM.sub.--002246.2.fwdarw.NP.sub.--002237.1. GenBank Accession No.
for potassium channel, subfamily K, member 6 (KCNK6, KCNK8; TWIK2;
K2p6.1) includes 1.NM.sub.--004823.1.fwdarw.NP.sub.--004814.1.
[0344] c. Determining Water Solubility of the Anesthetic
[0345] The water solubility of the anesthetic can be determined
using any method known in the art. For example, the water
solubility can be determined using a computer implemented
algorithm. One such algorithm is available through SciFinder
Scholar provided by the American Chemical Society and available on
the worldwide web at scifinder.cas.org. Water solubility values
using SciFinder Scholar are calculated using Advanced Chemistry
Development (ACD/Labs) Software V9.04 for Solaris (1994-2009
ACD/Labs). Solubility values are calculated at pH=7 in pure water
at 25.degree. C. Other computer-implemented algorithms for
determining the water solubility of an anesthetic find use and are
known in the art. For example, software for calculating water
solubility is also commercially available from Advanced Chemistry
Development of Toronto, Ontario, Canada (on the worldwide web at
acdlabs.com). Chemix software is available without charge and can
be downloaded from the internet at home.c2i.net/astandne.
[0346] Alternatively, the water solubility of a compound can be
empirically determined. For example, the conditions in which
anesthetic effects are measured in a biological system are usually
at pH (7.4), in a buffered electrolyte solution at 22-23.degree. C.
These differences likely account for the small variation in the
NMDA solubility cutoff for different hydrocarbon groups shown in
FIG. 4.
[0347] d. Determining the Specificity of the Anesthetic for the
Anesthetic-Sensitive Receptor
[0348] The water solubility of the anesthetic is compared with the
solubility cut-off or threshold concentration of an
anesthetic-sensitive receptor. If the molar water solubility of the
anesthetic is less than the solubility cut-off or threshold
concentration of an anesthetic-sensitive receptor, then the
anesthetic will not activate that anesthetic-sensitive receptor. If
the water solubility of the anesthetic is greater than the
solubility cut-off or threshold concentration of an
anesthetic-sensitive receptor, then the anesthetic can activate
that anesthetic-sensitive receptor.
[0349] For example, in some embodiments, an anesthetic with a molar
water solubility below a predetermined solubility threshold
concentration for Na.sub.v channels does not inhibit Na.sub.v
channels, but can inhibit NMDA receptors, potentiate two-pore
domain potassium channels (K.sub.2P), potentiate glycine receptors
and potentiate GABA.sub.A receptors.
[0350] In some embodiments, an anesthetic with a molar water
solubility below a predetermined solubility threshold concentration
for NMDA receptors does not inhibit Na.sub.v channels or inhibit
NMDA receptors, but can potentiate two-pore domain potassium
channels (K.sub.2P), potentiate glycine receptors and potentiate
GABA.sub.A receptors.
[0351] In some embodiments, an anesthetic with a molar water
solubility below a predetermined solubility threshold concentration
for two-pore domain potassium channels (K.sub.2P) does not inhibit
Na.sub.v channels, inhibit NMDA receptors or potentiate two-pore
domain potassium channel (K.sub.2P) currents, but can potentiate
glycine receptors and potentiate GABA.sub.A receptors.
[0352] In some embodiments, an anesthetic with a molar water
solubility below a predetermined solubility threshold concentration
for GABA.sub.A receptors does not inhibit Na.sub.v channels,
inhibit NMDA receptors, potentiate two-pore domain potassium
channel (K.sub.2P) currents, or potentiate GABA.sub.A receptors but
can potentiate glycine receptors.
[0353] In some embodiments, the anesthetic has a molar water
solubility below a predetermined solubility threshold concentration
for NMDA receptors (e.g., below about 1.1 mM) and potentiates
GABA.sub.A receptors but does not inhibit NMDA receptors. In some
embodiments, the anesthetic has a water solubility greater than a
predetermined solubility threshold concentration for NMDA receptors
(e.g., greater than about 1.1 mM) and both potentiates GABA.sub.A
receptors and inhibits NMDA receptors.
[0354] In various embodiments, the solubility threshold
concentration for NMDA receptors is in the range of between about
0.45 mM and about 2.8 mM, for example between about 1 mM and about
2 mM, for example, about, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM,
0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4
mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM or 2.0 mM. In some
embodiments, the predetermined solubility threshold concentration
for NMDA receptors is about 1.1 mM. In some embodiments, the
predetermined solubility threshold concentration for NMDA receptors
is about 2 mM. In some embodiments, the anesthetic has a molar
water solubility that is below the threshold water solubility
cut-off concentration of an NMDA receptor, and therefore does not
inhibit the NMDA receptor. In some embodiments, the anesthetic has
a water solubility that is below about 2 mM, for example, below
about 2.0 mM, 1.9 mM, 1.8 mM, 1.7 mM, 1.6 mM, 1.5 mM, 1.4 mM, 1.3
mM, 1.2 mM, 1.1 mM or 1.0 mM. In some embodiments, the anesthetic
has a water solubility that is above the threshold water solubility
cut-off concentration of an NMDA receptor, and therefore can
inhibit the NMDA receptor. In some embodiments, the anesthetic has
a molar water solubility that is above about 1.0 mM, for example,
above about 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM,
1.8 mM, 1.9 mM or 2.0 mM.
[0355] In various embodiments, the solubility threshold
concentration for two-pore domain potassium channels (K.sub.2P)
receptors is in the range of about 0.10-1.0 mM, for example, about
0.10 mM, 0.20 mM, 0.26 mM, 0.30 mM, 0.35 mM, 0.40 mM, 0.45 mM, 0.50
mM, 0.55 mM, 0.60 mM, 0.65 mM, 0.70 mM, 0.75 mM, 0.80 mM, 0.85 mM,
0.90 mM, 0.95 mM or 1.0 mM. In some embodiments, the predetermined
solubility threshold concentration for two-pore domain potassium
channels (K.sub.2P) receptors is about 0.26 mM. In some
embodiments, two-pore domain potassium channels (K.sub.2P) receptor
is a TREK or a TRESK receptor. In some embodiments, the anesthetic
has a molar water solubility that is below the threshold water
solubility cut-off concentration of a two-pore domain potassium
channels (K.sub.2P) receptor (e.g., below about 0.26 mM), and
therefore does not potentiate the two-pore domain potassium
channels (K.sub.2P) receptor. In some embodiments, the anesthetic
has a molar water solubility that is above the threshold water
solubility cut-off concentration of a two-pore domain potassium
channels (K.sub.2P) receptor (e.g., above about 0.26 mM), and
therefore can potentiate the two-pore domain potassium channels
(K.sub.2P) receptor.
[0356] In various embodiments, the solubility threshold
concentration for voltage-gated sodium channels (Na.sub.v) is in
the range of about 1.2 to about 1.9 mM, for example, about 1.2 mM,
1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM or 1.9 mM. In some
embodiments, the predetermined solubility threshold concentration
for voltage-gated sodium channels (Na.sub.v) is about 1.2 mM. In
some embodiments, the predetermined solubility threshold
concentration for voltage-gated sodium channels (Na.sub.v) is about
1.9 mM. In some embodiments, the anesthetic has a molar water
solubility that is below the threshold water solubility cut-off
concentration of a voltage-gated sodium channel (Na.sub.y) (e.g.,
below about 1.2 mM), and therefore does not inhibit the
voltage-gated sodium channel (Na.sub.v). In some embodiments, the
anesthetic has a water solubility that is above the threshold water
solubility cut-off concentration of a voltage-gated sodium channel
(Na.sub.v) (e.g., above about 1.9 mM) and therefore can inhibit the
voltage-gated sodium channel (Na.sub.v).
[0357] In various embodiments, the solubility threshold
concentration for GABA.sub.A receptors is in the range of about
50-100 .mu.M, for example, about 50 .mu.M, 60 .mu.M, 65 .mu.M, 68
.mu.M, 70 .mu.M, 75 .mu.M, 80 .mu.M, 85 .mu.M, 90 .mu.M, 95 .mu.M
or 100 .mu.M. In some embodiments, the predetermined solubility
threshold concentration for GABA.sub.A receptors is about 68 .mu.M.
In some embodiments, the anesthetic has a molar water solubility
that is below the threshold water solubility cut-off concentration
of a GABA.sub.A receptor (e.g., below about 68 .mu.M), and
therefore does not potentiate the GABA.sub.A receptor. In some
embodiments, the anesthetic has a water solubility that is above
the threshold water solubility cut-off concentration of a
GABA.sub.A receptor (e.g., above about 68 .mu.M), and therefore can
potentiate the GABA.sub.A receptor.
[0358] In various embodiments, the solubility threshold
concentration for glycine receptors is in the range of about
0.7-to-89 .mu.M, for example, about 0.7 .mu.M, 3.9 .mu.M, 7.8
.mu.M, 17 .mu.M, 31 .mu.M, 62 .mu.M, 89 .mu.M. In some embodiments,
the predetermined solubility threshold concentration for glycine
receptors is about 7.8 .mu.M. In some embodiments, the anesthetic
has a molar water solubility that is below the threshold water
solubility cut-off concentration of a glycine receptor, and
therefore does not activate the glycine receptor. In some
embodiments, the anesthetic has a water solubility that is above
the threshold water solubility cut-off concentration of a glycine
receptor.
[0359] e. Selecting the Desired Anesthetic
[0360] In some embodiments, the methods further comprise the step
of selecting an appropriate or desired anesthetic, e.g., based on
the subset of anesthetic-sensitive receptors that can be activated
by the anesthetic.
[0361] For example, the selected anesthetic can have a water
solubility below a predetermined solubility threshold concentration
for Na.sub.v channels (e.g., below about 1.2 mM), such that the
anesthetic does not inhibit Na.sub.v channels, but can inhibit NMDA
receptors, potentiate two-pore domain potassium channels
(K.sub.2P), potentiate glycine receptors and potentiate GABA.sub.A
receptors.
[0362] In some embodiments, the selected anesthetic can have a
water solubility below a predetermined solubility threshold
concentration for NMDA receptors (e.g., below about 1.1 mM) such
that the anesthetic does not inhibit Na.sub.v channels or inhibit
NMDA receptors, but can potentiate two-pore domain potassium
channels (K.sub.2P), potentiate glycine receptors and potentiate
GABA.sub.A receptors.
[0363] In some embodiments, the selected anesthetic can have a
water solubility below a predetermined solubility threshold
concentration for two-pore domain potassium channels (K.sub.2P)
(e.g., below about 0.26 mM) such that the anesthetic does not
inhibit Na.sub.v channels, inhibit NMDA receptors or potentiate
two-pore domain potassium channel (K.sub.2P) currents, but can
potentiate glycine receptors and potentiate GABA.sub.A
receptors.
[0364] In some embodiments, the selected anesthetic can have a
water solubility below a predetermined solubility threshold
concentration for GABA.sub.A receptors (e.g., below about 68 .mu.M)
such that the anesthetic does not inhibit Na.sub.v channels,
inhibit NMDA receptors, potentiate two-pore domain potassium
channel (K.sub.2P) currents, or potentiate GABA.sub.A receptors but
can potentiate glycine receptors.
[0365] In some embodiments, the selected anesthetic can have a
water solubility below a predetermined solubility threshold
concentration for NMDA receptors (e.g., below about 1.1 mM) such
that the anesthetic potentiates GABA.sub.A receptors but does not
inhibit NMDA receptors. In some embodiments, the anesthetic has a
water solubility greater than a predetermined solubility threshold
concentration for NMDA receptors (e.g., greater than about 1.1 mM)
and both potentiates GABA.sub.A receptors and inhibits NMDA
receptors.
[0366] In some embodiments, the selected anesthetic has a water
solubility such that the anesthetic does not activate NMDA
receptors, two-pore domain potassium channels (K.sub.2P),
voltage-gated sodium channels (Nav), or GABAA receptors, but can
activate glycine receptors. The anesthetic may have a water
solubility that is less than about 7.8 .mu.M.
[0367] The selected anesthetics usually have a water solubility
that is greater than 7.8 .mu.M.
VI. Methods of Modulating the Specificity of an Anesthetic for an
Anesthetic-Sensitive Receptor by Altering the Water Solubility of
the Anesthetic
[0368] The invention also provides methods for modulating (i.e.,
increasing or decreasing) the specificity of an anesthetic for an
anesthetic-sensitive receptor or a subset of anesthetic-sensitive
receptors by adjusting the water solubility of the anesthetic. The
anesthetic can be chemically modified or altered to increase or
decrease the water solubility and hence the specificity of the
anesthetic for the anesthetic-sensitive receptor or the subset of
anesthetic-sensitive receptors.
[0369] In various embodiments, this method can be performed by
determining the water solubility of the parent anesthetic and then
comparing the water solubility of the parent anesthetic threshold
cut-off value of an anesthetic-sensitive receptor, as described
above. If the water solubility of the anesthetic is below the water
solubility threshold cut-off concentration of the
anesthetic-sensitive receptor, then the anesthetic will not
modulate the receptor. If the capacity to modulate the
anesthetic-sensitive receptor is desired, the water solubility of
the anesthetic can be sufficiently increased, e.g., by chemically
modifying the parent anesthetic, such that the analog of the parent
anesthetic has a water solubility above the water solubility
threshold cut-off concentration of the receptor or the subset of
receptors of interest. In this case, the analog of the parent
anesthetic can modulate the anesthetic-sensitive receptor or a
subset of anesthetic-sensitive receptors of interest.
[0370] Conversely, if the water solubility of the anesthetic is
above the water solubility threshold cut-off concentration of the
anesthetic-sensitive receptor, then the anesthetic can modulate the
receptor. If the capacity to modulate the anesthetic-sensitive
receptor is not desired, then the water solubility of the
anesthetic can be sufficiently decreased, e.g., by chemically
modifying the parent anesthetic, such that the analog of the parent
anesthetic has a water solubility below the water solubility
threshold cut-off concentration of the anesthetic-sensitive
receptor or the subset of receptors of interest. In this case, the
analog of the parent anesthetic does not modulate the receptors or
subset of receptors of interest.
[0371] The water solubility of the parent anesthetic can be
adjusted using methods well known in the art. For example, the
parent anesthetic can be chemically modified. Substituents on the
parent anesthetic can be added, removed or changed, to increase or
decrease the water solubility of the compound, as desired. The
resulting analogs of the parent anesthetic either gain or lose the
functional ability to activate the anesthetic-sensitive receptor,
as desired, and have an increased or decreased water solubility,
respectively, in comparison to the parent anesthetic. The
anesthetic analogs of use retain the functional ability to effect
anesthesia. The potency and/or efficacy of the anesthetic analogs,
however, may be increased or decreased in comparison to the parent
anesthetic.
[0372] For example, to decrease the water solubility of the
anesthetic, polar or heteroatom substituents, e.g., hydroxyl or
amino groups, can be removed or substituted with more hydrophobic
substituents, e.g., a halogen or an alkyl group. Water solubility
can also be decreased, e.g., by increasing the number of carbons on
alkyl substituents, e.g., alkane, alkene, alkyne, alkoxy, etc. One,
two, three, four, or more carbons can be added to the alkyl
substituent, as needed, to decrease the water solubility of the
anesthetic, as desired.
[0373] Conversely, to increase the water solubility of the
anesthetic, hydrophobic substituents, e.g., a halogen or an alkyl
group, can be removed or substituted with polar or heteroatom
substituents, e.g., hydroxyl or amino groups. Water solubility can
also be increased, e.g., by decreasing the number of carbons on
alkyl substituents, e.g., alkane, alkene, alkyne, alkoxy, etc. One,
two, three, four, or more carbons can be removed from the alkyl
substituent, as needed, to increase the water solubility of the
anesthetic, as desired.
[0374] For example, in some embodiments, the anesthetic is adjusted
to have a water solubility below a predetermined solubility
threshold concentration for NMDA receptors (e.g., below about 1.1
mM) such that the anesthetic does not inhibit Na.sub.v channels or
inhibit NMDA receptors, but can potentiate two-pore domain
potassium channels (K.sub.2P), potentiate glycine receptors and
potentiate GABA.sub.A receptors. The water solubility threshold
concentrations for the different anesthetic-sensitive receptors are
as described above and herein.
[0375] In some embodiments, the anesthetic is adjusted to have a
water solubility below a predetermined solubility threshold
concentration for two-pore domain potassium channels (K.sub.2P)
(e.g., below about 0.26 mM) such that the anesthetic does not
inhibit Na.sub.v channels, inhibit NMDA receptors or potentiate
two-pore domain potassium channel (K.sub.2P) currents, but can
potentiate glycine receptors and potentiate GABA.sub.A
receptors.
[0376] In some embodiments, the anesthetic is adjusted to have a
water solubility below a predetermined solubility threshold
concentration for voltage-gated sodium channels (Na.sub.v) (e.g.,
below about 1.2 mM) such that the anesthetic does not inhibit
Na.sub.v channels, but can inhibit NMDA receptors, potentiate
two-pore domain potassium channels (K.sub.2P), potentiate glycine
receptors and potentiate GABA.sub.A receptors.
[0377] In some embodiments, the anesthetic is adjusted to have a
water solubility above a predetermined solubility threshold
concentration for NMDA receptors (e.g., above about 1.1 mM) such
that the anesthetic can both potentiate GABA.sub.A receptors and
inhibit NMDA receptors.
[0378] In various embodiments, the anesthetic is adjusted to have a
water solubility that is below the threshold water solubility
cut-off concentration of an NMDA receptor, and therefore does not
activate the NMDA receptor. In some embodiments, an anesthetic is
adjusted to have a water solubility that is below about 2 mM, for
example, below about 2.0 mM, 1.9 mM, 1.8 mM, 1.7 mM, 1.6 mM, 1.5
mM, 1.4 mM, 1.3 mM, 1.2 mM, 1.1 mM or 1.0 mM. In some embodiments,
an anesthetic is adjusted to have a water solubility that is below
about 1.1 mM. In some embodiments, the anesthetic is adjusted to
have a water solubility that is above the threshold water
solubility cut-off concentration of an NMDA receptor. In some
embodiments, an anesthetic is adjusted to have a water solubility
that is above about 1.0 mM, for example, above about 1.1 mM, 1.2
mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM or 2.0
mM. In some embodiments, an anesthetic is adjusted to have a water
solubility that is above about 1.1 mM.
[0379] In some embodiments, the anesthetic is adjusted to have a
water solubility that is below the threshold water solubility
cut-off concentration of a two-pore domain potassium channels
(K.sub.2P) receptor, and therefore does not potentiate the two-pore
domain potassium channels (K.sub.2P) receptor. In some embodiments,
the anesthetic is adjusted to have a water solubility that is below
about 0.10 mM, 0.20 mM, 0.26 mM, 0.30 mM, 0.35 mM, 0.40 mM, 0.45
mM, 0.50 mM, 0.55 mM, 0.60 mM, 0.65 mM, 0.70 mM, 0.75 mM, 0.80 mM,
0.85 mM, 0.90 mM, 0.95 mM or 1.0 mM. In some embodiments, the
anesthetic is adjusted to have a water solubility that is below
about 0.26 mM. In some embodiments, the anesthetic is adjusted to
have a water solubility that is above the threshold water
solubility cut-off concentration of a two-pore domain potassium
channels (K.sub.2P) receptor, and therefore can potentiate the
two-pore domain potassium channels (K.sub.2P) receptor. In some
embodiments, the anesthetic is adjusted to have a water solubility
that is above about 0.10 mM, 0.20 mM, 0.26 mM, 0.30 mM, 0.35 mM,
0.40 mM, 0.45 mM, 0.50 mM, 0.55 mM, 0.60 mM, 0.65 mM, 0.70 mM, 0.75
mM, 0.80 mM, 0.85 mM, 0.90 mM, 0.95 mM or 1.0 mM. In some
embodiments, the anesthetic is adjusted to have a water solubility
that is above about 0.26 mM. In some embodiments, two-pore domain
potassium channels (K.sub.2P) receptor is a TREK or a TRESK
receptor.
[0380] In some embodiments, the anesthetic is adjusted to have a
water solubility that is below the threshold water solubility
cut-off concentration of a voltage-gated sodium channel (Na.sub.v),
and therefore does not inhibit the voltage-gated sodium channel
(Na.sub.v). In some embodiments, the anesthetic is adjusted to have
a water solubility that is below about 1.2 mM, 1.3 mM, 1.4 mM, 1.5
mM, 1.6 mM, 1.7 mM, 1.8 mM or 1.9 mM. In some embodiments, the
anesthetic is adjusted to have a water solubility that is below
about 1.2 mM. In some embodiments, the anesthetic is adjusted to
have a water solubility that is above the threshold water
solubility cut-off concentration of a voltage-gated sodium channel
(Na.sub.v), and therefore can inhibit the voltage-gated sodium
channel (Na.sub.v). In some embodiments, the anesthetic is adjusted
to have a water solubility that is above about 1.2 mM, 1.3 mM, 1.4
mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM or 1.9 mM. In some embodiments,
the anesthetic is adjusted to have a water solubility that is above
about 1.9 mM.
[0381] In some embodiments, the anesthetic is adjusted to have a
water solubility that is below the threshold water solubility
cut-off concentration of a GABA.sub.A receptor, and therefore does
not potentiate the GABA.sub.A receptor. In some embodiments, the
anesthetic is adjusted to have a water solubility that is below
about 50 .mu.M, 60 .mu.M, 65 .mu.M, 68 .mu.M, 70 .mu.M, 75 .mu.M,
80 .mu.M, 85 .mu.M, 90 .mu.M, 95 .mu.M or 100 .mu.M. In some
embodiments, the anesthetic is adjusted to have a water solubility
that is below about 68 .mu.M. In some embodiments, the anesthetic
is adjusted to have a water solubility that is above the threshold
water solubility cut-off concentration of a GABA.sub.A receptor,
and therefore can potentiate the GABA.sub.A receptor. In some
embodiments, the anesthetic is adjusted to have a water solubility
that is above about 50 .mu.M, 60 .mu.M, 65 .mu.M, 68 .mu.M, 70
.mu.M, 75 .mu.M, 80 .mu.M, 85 .mu.M, 90 .mu.M, 95 .mu.M or 100
.mu.M. In some embodiments, the anesthetic is adjusted to have a
water solubility that is above about 68 .mu.M.
[0382] In some embodiments, the anesthetic is adjusted to have a
water solubility that is below the threshold water solubility
cut-off concentration of a glycine receptor, and therefore does not
potentiate the glycine receptor. In some embodiments, the
anesthetic is adjusted to have a water solubility that is above the
threshold water solubility cut-off concentration of a glycine
receptor, and therefore can potentiate the glycine receptor. The
solubility cut-off for the glycine receptor is about 7.8 .mu.M, but
may range between 0.7 and 89 .mu.M.
[0383] In some embodiments, the methods further comprise the step
of selecting the anesthetic analog with the desired water
solubility. In some embodiments, the methods further comprise the
step of administering the anesthetic analog, as described above and
herein.
EXAMPLES
[0384] The following examples are offered to illustrate, but not to
limit the claimed invention.
Example 1
[0385] Hydrocarbon Molar Water Solubility Predicts NMDA Vs.
GABA.sub.A Receptor Modulation
[0386] Background:
[0387] Many anesthetics modulate 3-transmembrane (such as NMDA) and
4-transmembrane (such as GABA.sub.A) receptors. Clinical and
experimental anesthetics exhibiting receptor family specificity
often have low water solubility. We determined that the molar water
solubility of a hydrocarbon could be used to predict receptor
modulation in vitro.
[0388] Methods:
[0389] GABA.sub.A (.alpha..sub.1.beta..sub.2.gamma..sub.2s) or NMDA
(NR1/NR2A) receptors were expressed in oocytes and studied using
standard two-electrode voltage clamp techniques. Hydrocarbons from
14 different organic functional groups were studied at saturated
concentrations, and compounds within each group differed only by
the carbon number at the w-position or within a saturated ring. An
effect on GABA.sub.A or NMDA receptors was defined as a 10% or
greater reversible current change from baseline that was
statistically different from zero.
[0390] Results:
[0391] Hydrocarbon moieties potentiated GABA.sub.A and inhibited
NMDA receptor currents with at least some members from each
functional group modulating both receptor types. A water solubility
cut-off for NMDA receptors occurred at 1.1 mM with a 95% CI=0.45 to
2.8 mM. NMDA receptor cut-off effects were not well correlated with
hydrocarbon chain length or molecular volume. No cut-off was
observed for GABA.sub.A receptors within the solubility range of
hydrocarbons studied.
[0392] Conclusions:
[0393] Hydrocarbon modulation of NMDA receptor function exhibits a
molar water solubility cut-off. Differences between unrelated
receptor cut-off values suggest that the number, affinity, or
efficacy of protein-hydrocarbon interactions at these sites likely
differ.
Methods
[0394] Oocyte Collection and Receptor Expression.
[0395] An ovary from tricaine-anesthetized Xenopus laevis frogs was
surgically removed using a protocol approved by the Institutional
Animal Care and Use Committee at the University of California,
Davis. Following manual disruption of the ovarian lobule septae,
the ovary was incubated in 0.2% Type I collagenase (Worthington
Biochemical, Lakewood, N.J.) to defolliculate oocytes which were
washed and stored in fresh and filtered modified Barth's solution
composed of 88 mM NaCl, 1 mM KCl, 2.4 mM NaHCO.sub.3, 20 mM HEPES,
0.82 mM MgSO.sub.4, 0.33 mM Ca(NO.sub.3).sub.2, 0.41 mM CaCl.sub.2,
5 mM sodium pyruvate, gentamycin, penicillin, streptomycin, and
corrected to pH=7.4. All salts and antibiotics were A.C.S. grade
(Fisher Scientific, Pittsburgh, Pa.).
[0396] Clones used were provided as a gift from Dr. R. A. Harris
(University of Texas, Austin) and were sequenced and compared to
references in the National Center for Biotechnology Information
database to confirm the identity of each gene. GABA.sub.A receptors
were expressed using clones for the human GABA.sub.A .alpha.1 and
the rat GABA.sub.A .beta.2 and .gamma.2s subunits in pCIS-II
vectors. Approximately 0.25-1 ng total plasmid mixture containing
either .alpha.1, .beta.2, or .gamma.2 genes in a respective ratio
of 1:1:10 was injected intranuclearly through the oocyte animal
pole and studied 2-4 days later. These plasmid ratios ensured
incorporation of the .gamma.-subunit into expressed receptors, as
confirmed via receptor potentiation to 10 .mu.M chlordiazepoxide or
insensitivity to 10 .mu.M zinc chloride during co-application with
GABA. In separate oocytes, glutamate receptors were expressed using
rat NMDA NR1 clones in a pcDNA3 vector and rat NMDA NR2A clones in
a Bluescript vector. RNA encoding each subunit was prepared using a
commercial transcription kit (T7 mMessage mMachine, Ambion, Austin,
Tex.) was mixed in a 1:1 ratio, and 1-10 ng of total RNA was
injected into oocytes and studied 1-2 days later. Oocytes injected
with similar volumes of water served as controls.
[0397] GABA.sub.A Receptor Electrophysiology Studies.
[0398] Oocytes were studied in a 250 .mu.L linear-flow perfusion
chamber with solutions administered by syringe pump at 1.5 ml/min
with gastight glass syringes and Teflon tubing. Oocyte GABAA
currents were studied using standard two-electrode voltage clamping
techniques at a holding potential of 80 mV using a 250 .mu.L
channel linear-flow perfusion chamber with solutions administered
by syringe pump at 1.5 mL/min.
[0399] Frog Ringer's (FR) solution composed of 115 mM NaCl, 2.5 mM
KCl, 1.8 mM CaCl.sub.2, and 10 mM HEPES prepared in 18.2 M.OMEGA.
H.sub.2O and filtered and adjusted to pH=7.4 was used to perfuse
oocytes. Agonist solutions also contained an EC 10-20 of
4-aminobutanoic acid (FR-GABA) (Brosnan, et al., Anesth Analg
(2006) 103:86-91; Yang, et al., Anesth Analg (2007) 105:673-679;
Yang, et al., Anesth Analg (2007) 105:393-396). After FR perfusion
for 5 min, oocytes were exposed to 30 sec FR-GABA followed by
another 5 min FR washout; this was repeated until stable
GABA.sub.A-elicited peaks were obtained. Next, FR containing a
saturated solution of the study drug (Table 2)--or for gaseous
study compounds a vapor pressure equal to 90% of barometric
pressure with balance oxygen--was used to perfuse the oocyte
chamber for 2 min followed by perfusion with a FR-GABA solution
containing the identical drug concentration for 30 sec. FR was next
perfused for 5 min to allow drug washout, and oocytes were finally
perfused with FR-GABA for 30 sec to confirm return of currents to
within 10% of the initial baseline response.
TABLE-US-00002 TABLE 2 MW Solubility Carbon Volume Purity Compound
CAS# (amu) P.sub.vap (mmHg) (M) (#) (.ANG..sup.3) Source (%)
Alcohols 1-decanol 112-30-1 158.28 1.48 .times. 10.sup.-2 6.5
.times. 10.sup.-4 10 317 Aldrich >99 1-undecanol 112-42-5 172.31
5.10 .times. 10.sup.-3 1.7 .times. 10.sup.-4 11 344 Acros 98
1-dodecanol 112-53-8 186.33 2.09 .times. 10.sup.-3 4.1 .times.
10.sup.-5 12 372 TCI 99 Alkanes butane 106-97-8 58.12 1.92 .times.
10.sup.3 1.4 .times. 10.sup.-3 4 156 Matheson 99.99 pentane
109-66-0 72.15 5.27 .times. 10.sup.2 4.3 .times. 10.sup.-4 5 184
Aldrich >99 hexane 110-54-3 86.18 1.51 .times. 10.sup.2 1.2
.times. 10.sup.-4 6 211 Acros >99 Aldehydes octanal 124-13-0
128.21 2.07 .times. 10.sup.0 5.4 .times. 10.sup.-3 8 262 Aldrich 99
nonanal 124-19-6 142.24 5.32 .times. 10.sup.-1 2.3 .times.
10.sup.-3 9 289 Aldrich 95 decanal 112-31-2 156.27 2.07 .times.
10.sup.-1 9.8 .times. 10.sup.-4 10 316 Aldrich 98 undecanal
112-44-7 170.29 8.32 .times. 10.sup.-2 4.2 .times. 10.sup.-4 11 344
Aldrich 97 Alkenes 1-pentene 109-67-1 70.13 6.37 .times. 10.sup.2
1.4 .times. 10.sup.-3 5 176 Aldrich 99 1-hexene 592-41-6 84.16 1.88
.times. 10.sup.2 4.2 .times. 10.sup.-4 6 203 Aldrich >99 Alkynes
1-hexyne 693-02-7 82.14 1.35 .times. 10.sup.2 2.9 .times. 10.sup.-3
6 184 Aldrich 97 1-heptyne 628-71-7 96.17 4.35 .times. 10.sup.1 6.6
.times. 10.sup.-4 7 212 Acros 99 1-octyne 629-05-0 110.2 1.44
.times. 10.sup.1 1.9 .times. 10.sup.-4 8 239 Acros 99 Amines
1-octadecanamine 124-30-1 269.51 4.88 .times. 10.sup.-5 1.3 .times.
10.sup.-3 18 546 TCI 97 1-eicosanamine 10525-37-8 297.56 8.96
.times. 10.sup.-6 2.7 .times. 10.sup.-4 20 601 Rambus 95 Benzenes
1,3-dimethylbenzene 108-38-3 106.17 7.61 .times. 10.sup.0 1.2
.times. 10.sup.-3 8 202 Aldrich >99 1,3-diethylbenzene 141-93-5
134.22 1.15 .times. 10.sup.0 6.6 .times. 10.sup.-5 10 257 Fluka
>99 Cycloalkanes cyclopentane 287-92-3 70.13 3.14 .times.
10.sup.2 3.3 .times. 10.sup.-3 5 147 Aldrich >99 cyclohexane
110-82-7 84.16 9.37 .times. 10.sup.1 1.0 .times. 10.sup.-3 6 176
Aldrich >99.7 Ethers dibutylether 142-96-1 130.23 7.10 .times.
10.sup.0 1.6 .times. 10.sup.-2 8 277 Aldrich 99.3 dipentylether
693-65-2 158.28 1.00 .times. 10.sup.0 3.0 .times. 10.sup.-3 10 331
Fluka >98.5 dihexylether 112-58-3 186.33 1.48 .times. 10.sup.-1
5.8 .times. 10.sup.-4 12 386 Aldrich 97 Esters ethyl heptanoate
106-30-9 158.24 6.02 .times. 10.sup.-1 5.4 .times. 10.sup.-3 9 299
MP Bio 99 ethyl octanoate 106-32-1 172.26 2.24 .times. 10.sup.-1
2.1 .times. 10.sup.-3 10 327 Aldrich >99 ethyl decanoate
110-38-3 200.32 3.39 .times. 10.sup.-2 4.4 .times. 10.sup.-4 12 381
TCI 98 Haloalkanes 1-fluoropentane 592-50-7 90.14 1.84 .times.
10.sup.2 3.9 .times. 10.sup.-3 5 193 Aldrich 98 1-fluorohexane
373-14-8 104.17 6.06 .times. 10.sup.1 1.2 .times. 10.sup.-3 6 220
Acros >99 1-fluoroctane 463-11-6 132.22 7.09 .times. 10.sup.0
1.3 .times. 10.sup.-4 8 275 Aldrich 98 Ketones 2-decanone 693-54-9
156.27 2.48 .times. 10.sup.-1 3.2 .times. 10.sup.-3 10 316 TCI
>99 2-undecanone 112-12-9 170.29 9.78 .times. 10.sup.-2 1.4
.times. 10.sup.-3 11 343 Acros 98 2-dodecanone 6175-49-1 184.32
3.96 .times. 10.sup.-2 5.8 .times. 10.sup.-4 12 371 TCI 95 Sulfides
1-(ethylthio)-hexane 7309-44-6 146.29 8.16 .times. 10.sup.-1 2.8
.times. 10.sup.-3 8 289 Pfaltz 97 1-(ethylthio)-octane 3698-94-0
174.35 1.08 .times. 10.sup.-1 5.0 .times. 10.sup.-4 10 344 Pfaltz
97 Thiols 1-pentanethiol 110-66-7 104.21 1.42 .times. 10.sup.1 1.5
.times. 10.sup.-3 5 207 Aldrich 98 1-hexanethiol 111-31-9 118.24
4.50 .times. 10.sup.0 5.1 .times. 10.sup.-4 6 235 TCI 96
[0400] Source, purity and physical properties of study compounds.
Chemical Abstracts Service number (CAS#), molecular weight (MW),
vapor pressure at 25.degree. C. (Pvap), molar solubility in pure
water at pH=7, and molecular volume are calculated estimates
(rather than measured values) referenced by SciFinder Scholar.
[0401] NMDA Receptor Electrophysiology Studies.
[0402] Methods for measurement of whole-cell NMDA receptor currents
have been described (Brosnan, et al., Br J Anaesth (2008)
101:673-679; Brosnan, et al., Anesth Analg (2011)112:568-573).
Briefly, baseline perfusion solutions were the same as for
GABA.sub.A with the substitution of equimolar BaCl.sub.2 for
calcium salts and the addition of 0.1 mM EGTA; this constituted
barium frog Ringer's solution (BaFR). Agonist solutions for NMDA
studies also contained 0.1 mM glutamate (E) and 0.01 mM glycine (G)
to constitute a BaFREG solution.
[0403] The syringe pump and perfusion chamber apparatus as well as
the clamp holding potential and baseline-agonist exposure protocols
were identical to that described for the GABA.sub.A studies. The
same test compounds, concentrations, and preparative methods were
used in NMDA voltage clamp studies as in the GABA.sub.A voltage
clamp studies (Table 2).
[0404] Response Calculations and Data Analysis.
[0405] Modulating drug responses were calculated as the percent of
the control (baseline) peak as follows: 100I.sub.D/I.sub.B, where
I.sub.D and I.sub.B were the peak currents measured during
agonist+drug and agonist baseline perfusions, respectively. When
present, direct receptor activation by a drug was similarly
calculated as a percent of the agonist response. Average current
responses for each drug and channel were described by mean.+-.SD. A
lack of receptor response (cut-off) was defined as a <10% change
from baseline current that was statistically indistinguishable from
zero using a two-tailed Student t-test. Hence, drug responses
.gtoreq.110% of the baseline peak showed potentiation of receptor
function, and drug responses .ltoreq.90% of the baseline peak
showed inhibition of receptor function.
[0406] The log.sub.10 of the calculated solubility (log.sub.10S)
for compounds immediately below and above the cut-off for each
hydrocarbon functional group were used to determine the receptor
cut-off. For each hydrocarbon, there was a "grey area" of
indeterminate solubility effect (FIG. 3) between sequentially
increasing hydrocarbon chain length. Mean solubility cut-offs were
calculated as the average log.sub.10S for the least soluble
compound that modulated receptor function and the most soluble
neighboring compound for which no effect was observed. From this
result, a 95% confidence interval for log.sub.10S was calculated
for receptor solubility cut-offs.
Results
[0407] Hydrocarbon effects on NMDA and GABA.sub.A receptors are
summarized in Table 3, and sample recordings are presented in FIG.
3. All of the compounds tested positively modulated GABAA receptor
function, and a few of the 5-to-6 carbon compounds caused mild
direct GABAA receptor activation, particularly the 1-fluoroalkanes
and thiols. Mild direct receptor activation also occurred with
dibutylether. With the exception of the aldehydes, alkynes, and
cycloalkanes, GABAA receptor inhibition tended to decrease with
increasing hydrocarbon chain length. No water solubility cut-off
effect was observed for GABAA receptors for the compounds
tested.
TABLE-US-00003 TABLE 3 NMDA GABA.sub.A % Direct % Agonist Drug %
Direct % Agonist Drug Compound Effect Effect Response Effect Effect
Response Alcohols 1-decanol none 70 .+-. 3 -- none 386 .+-. 20 +
1-undecanol none 101 .+-. 2 0 none 181 .+-. 13 + 1-dodecanol none
98 .+-. 1 0 none 177 .+-. 4 + Alkanes butane none 7 .+-. 2 -- none
623 .+-. 68 + pentane none 94 .+-. 3 0 none 321 .+-. 10 + hexane
none 100 .+-. 1 0 none 129 .+-. 5 + Aldehydes octanal none 71 .+-.
3 -- 6 .+-. 3 357 .+-. 20 + nonanal none 104 .+-. 2 0 none 219 .+-.
29 + decanal none 97 .+-. 3 0 none 159 .+-. 5 + undecanal none 97
.+-. 8 0 none 299 .+-. 29 + Alkenes 1-pentene none 69 .+-. 1 -- 2
.+-. 3 453 .+-. 38 + 1-hexene none 97 .+-. 0 0 none 132 .+-. 2 +
Alkynes 1-hexyne none 41 .+-. 6 -- 5 .+-. 2 418 .+-. 21 + 1-heptyne
none 68 .+-. 10 -- none 172 .+-. 8 + 1-octyne none 96 .+-. 2 0 none
259 .+-. 11 + Amines 1-octadecanamine none 73 .+-. 4 -- none 146
.+-. 5 + 1-eicosanamine none 108 .+-. 1 0 none 166 .+-. 7 +
Benzenes 1,3-dimethylbenzene none 58 .+-. 3 -- none 366 .+-. 21 +
1,3-diethylbenzene none 101 .+-. 2 0 none 305 .+-. 24 +
Cycloalkanes cyclopentane none 83 .+-. 2 -- 3 .+-. 2 196 .+-. 11 +
cyclohexane none 101 .+-. 2 0 none 421 .+-. 17 + Ethers
dibutylether none 59 .+-. 4 -- 14 .+-. 13 347 .+-. 33 +
dipentylether none 97 .+-. 2 0 none 211 .+-. 9 + dihexylether none
112 .+-. 4 0 none 113 .+-. 1 + Esters ethyl heptanoate none 78 .+-.
3 -- none 370 .+-. 34 + ethyl octanoate none 90 .+-. 1 -- none 285
.+-. 18 + ethyl decanoate none 98 .+-. 1 0 none 137 .+-. 2 +
Haloalkanes 1-fluoropentane none 76 .+-. 2 -- none 539 .+-. 35 +
1-fluorohexane none 101 .+-. 1 0 11 .+-. 4 207 .+-. 13 +
1-fluoroctane none 98 .+-. 1 0 none 182 .+-. 18 + Ketones
2-decanone none 81 .+-. 1 -- none 476 .+-. 52 + 2-undecanone none
98 .+-. 2 0 none 230 .+-. 16 + 2-dodecanone none 97 .+-. 3 0 none
325 .+-. 30 + Sulfides 1-(ethylthio)-hexane none 87 .+-. 1 -- none
350 .+-. 57 + 1-(ethylthio)-octane none 101 .+-. 1 0 none 120 .+-.
3 + Thiols 1-pentanethiol none 85 .+-. 4 -- 22 .+-. 8 466 .+-. 57 +
1-hexanethiol none 102 .+-. 3 0 8 .+-. 2 290 .+-. 41 +
[0408] Mean responses (.+-.SEM) produced by 14 different functional
groups on NMDA and GABAA receptor modulation, expressed as a
percent of the control agonist peak, using standard two-electrode
voltage clamp techniques with 5-6 oocytes each. The % Direct Effect
is the drug response without co-administration of the receptor
agonist. The % Agonist Effect is the drug response with
co-administration of agonist (glutamate and glycine for NMDA
receptors; .gamma.-aminobutyric acid for GABAA receptors). The Drug
Response denotes inhibition (-) for drug+agonist responses less
than the control agonist peak, potentiation (+) for drug+agonist
responses greater than the control agonist peak, and no response
(0) for drug+agonist responses that differ by <10% from the
control agonist peak.
[0409] In contrast, NMDA receptors currents were decreased by the
shorter hydrocarbons within each functional group (Table 2), but
lengthening the hydrocarbon chain eventually produced a null
response--a cut-off effect. No direct hydrocarbon effects on NMDA
receptor function were detected in the absence of glutamate and
glycine agonist.
[0410] The cut-off effect for NMDA receptor current modulation was
associated with a hydrocarbon water solubility of 1.1 mM with a 95%
confidence interval between 0.45 mM and 2.8 mM (FIG. 4). More
soluble hydrocarbons consistently inhibited NMDA receptor currents
when applied at saturated aqueous concentrations, and hydrocarbons
below this range had no appreciable effect on NMDA receptor
function. Moreover, during the course of the study, water
solubility was sufficiently predictive of an NMDA receptor cut-off
so as to require identify and testing of only single pair of
compounds bracketing this critical solubility value, as occurred
with the alkenes, amines, cyclic hydrocarbons, and
sulfur-containing compounds.
[0411] Increasing hydrocarbon chain length decreases water
solubility, but also increases molecular size. However, when
graphed as a function of either carbon number (FIG. 5) or molecular
volume (FIG. 6), the observed NMDA receptor cut-off effects show no
consistent pattern. For example, the n-alkanes, 1-alkenes, and
1-alkynes show progressive lengthening of the hydrocarbon chain
cut-off, presumably as a result of the increasing aqueous
solubility conferred by the double and triple carbon bonds,
respectively. There was also tremendous variation in molecular size
of compounds exhibiting NMDA receptor cut-off. Alkanes exhibited
NMDA receptor cut-off between butane and pentane, respectively 4
and 5 carbons in length, whereas the primary amines exhibited
cut-off between 1-octadecanamine and 1-eicosanamine, respectively
18 and 20 carbons in length. As expected, the molecular volume of
these compounds associated with NMDA receptor cut-off is also quite
different, with the primary amine being over 3 times larger than
the alkane.
Discussion
[0412] NMDA receptor modulation is associated with an approximate
1.1 mM water solubility cut-off (FIG. 4). In contrast, GABA.sub.A
receptors potentiated all studied compounds, suggesting that either
a GABA.sub.A cut-off occurs at a lower water solubility value or
possibly that GABA.sub.A receptors lack such a cut-off. Increasing
a single hydrocarbon length to find a receptor cut-off effect
introduces confounding factors of carbon number and molecular
volume that could in turn be responsible for the cut-off effect
(Eger, et al., Anesth Analg (1999) 88:1395-1400; Jenkins, J
Neurosci (2001) 21:RC136; Wick, Proc Natl Acad Sci USA (1998)
95:6504-6509; Eger, Anesth Analg (2001) 92:1477-1482). An aggregate
comparison of cut-off values for all functional groups as a
function of carbon number (FIG. 5) or molecular volume (FIG. 6)
shows no discernible pattern, suggesting that these physical
properties are unlikely the primary limiting factors for
drug-receptor modulation.
[0413] Nonetheless, although the correlation between cut-off and
molar water solubility is very good, it is not perfect. Some
variability is due simply to the lack of compounds of intermediate
solubility within a functional group series. For example,
pentanethiol inhibited NMDA receptors, whereas the 1-carbon longer
hexanethiol did not (Table 3). This pre-cut-off thiol is nearly
3-times more soluble in water than its post-cut-off cognate; yet it
is not possible to obtain a more narrowly defined cut-off
delineation for 1-thiols. Even larger variability was observed with
the dialkylbenzene series, to which 1 additional carbon was added
to each 1- and 3-alkyl group. The solubility ratio between the NMDA
antagonist 1,3-dimethylbenzene and its cut-off cognate
1,3-diethylbenzene is more than 18 (Table 3).
[0414] Variability about the molar water solubility NMDA receptor
cut-off may also have arisen from the use of calculated, rather
than measured, values for hydrocarbon molar water solubility.
Aqueous solubility is difficult to measure accurately, particularly
for poorly soluble substances. Calculated solubilities are more
accurate for small uncharged compounds, but still can have an
absolute error within 1 log unit (Delaney, et al., Drug Discov
Today (2005) 10:289-295). However, even predicted values for
nonpolar n-alkanes may show large deviations from experimental data
as the hydrocarbon chain length increases (Ferguson, J Phys Chem B
(2009) 113:6405-6414).
[0415] Furthermore, the molar solubility values used in the present
study were calculated for pure water at 25.degree. C. and at
pH=7.0. These were not the conditions under which drug-receptor
effects were studied. Ringer's oocyte perfusates contained buffers
and physiologic concentrations of sodium, potassium, and chloride
resulting in a 250 mOsm solution. The solubility of haloether and
haloalkane anesthetic vapors vary inversely with osmolarity
(Lerman, et al., Anesthesiology (1983) 59:554-558), as do the
water-to-saline solubility ratio of benzenes, amines, and ketones
(Long, et al., Chem Rev (1952) 51:119-169). The presence of salts
could have caused overestimation of aqueous solubility for some
compounds when using values calculated for pure water. Likewise,
solubility is also temperature-dependent. Studies were conducted at
22.degree. C.; solubility of gases in water should be greater than
values calculated at 25.degree. C. In contrast, most solutes used
in the present study have negative enthalpy for dissolution
(Abraham, et al., J Am Chem Soc (1982) 104:2085-2094), so
solubility should be decreased at the lower ambient temperature.
The reverse should occur for exothermic solutions, as predicted by
the Le Chatelier principle. As for hydronium ion concentration, the
solubility of most study compounds is trivially affected at pH
values between 7-to-8. However, hydrocarbons containing an amine
group have pKa values that are closer to physiologic pH, and the
calculated aqueous solubility of 1-eicosanamine and
1-octadecanamine (Table 2) decreases by about 66% as pH increases
from 7 to 8. Calculated molar water solubilities for the amines in
this study were probably modestly overestimated at a physiologic pH
equal to 7.4.
[0416] Despite these inaccuracies inherent in calculated rather
than experimentally measured values, an association between molar
water solubility and NMDA receptor modulation cut-off remains
evident. Anesthetics exhibit low-affinity binding on receptors;
these weak interactions are inconsistent with an induced fit
binding. Rather, anesthetics likely bind to pre-existing pockets
and surfaces on or within the protein (Trudell, et al., Br J
Anaesth (2002) 89:32-40). A critical water solubility for
modulation implies that critical modulation sites are either
hydrophilic or amphiphilic. Hydrocarbons act as hydrogen bond
donors--or in the case of electrophiles, as hydrogen bond
acceptors--with amino acid residues on anesthetic-sensitive
receptors, resulting in displacement of water molecules from these
binding pockets and alteration of protein function (Bertaccini, et
al., Anesth Analg (2007) 104:318-324; Abraham, et al., J Pharm Sci
(1991) 80:719-724; Streiff, et al., J Chem Inf Model (2008)
48:2066-2073). These low energy anesthetic-protein interactions are
postulated to be enthalpically favorable since the displaced water
molecules should be better able to hydrogen bond with like
molecules in the bulk solvent rather than with amino acids
(Bertaccini, et al., Anesth Analg (2007) 104:318-324; Streiff, et
al., J Chem Inf Model (2008) 48:2066-2073). Halothane and
isoflurane both have been shown to bind in water accessible pockets
formed between .alpha.-helices in .delta.-subunits of the nicotinic
acetylcholine receptor (Chiara, et al., Biochemistry (2003)
42:13457-13467), a member of the 4-transmembrane receptor
superfamily that includes the GABA.sub.A receptor. Models of
nicotinic acetylcholine receptors and GABA.sub.A receptors further
suggest that endogenous agonist or anesthetic binding might
increase water accumulation in hydrophilic pockets and increase the
number and accessibility of hydrophilic sites that are important
for channel gating (Willenbring, et al., Phys Chem Chem Phys (2010)
12:10263-10269; Williams, et al., Biophys J (1999) 77:2563-2574).
However, molecules that are insufficiently water soluble may not be
able to displace enough water molecules at enough critical sites in
order to modulate channel function.
[0417] NMDA receptor modulation by inhaled anesthetics such as
isoflurane, xenon, and carbon dioxide occurs--at least in part--at
hydrophilic agonist binding sites (Brosnan, et al., Anesth Analg
(2011) 112:568-573; Dickinson, et al., Anesthesiology (2007)
107:756-767). Yet despite evidence that hydrophilic interactions
are important to hydrocarbon modulation of anesthetic-sensitive
receptors, the minimum hydrocarbon hydrophilicity required to exert
anesthetic-like effects is different between NMDA and GABA.sub.A
receptors. As these receptors belong to different and
phylogenetically distinct superfamilies, it seems likely that
either the number of displaced water molecules required to effect
modulation and/or the relative affinities of the hydrocarbon versus
water molecule for a critical hydrophilic protein pocket and/or the
number of hydrophilic sites necessary for allosteric modulation
should also be different between proteins. Put another way, there
is a minimum number of hydrocarbon molecules--no matter the
type--that is required to interact with NMDA receptors to alter ion
channel conductance, and this number is significantly greater than
that necessary to alter GABA.sub.A receptor ion channel
conductance. Implied is that other ion channels should exhibit
hydrocarbon cut-off effects that correlate with molar water
solubility, and these solubility cut-off values will likely be more
similar between channels having a common phylogeny than cut-off
values between distantly or unrelated proteins.
[0418] Hydrocarbons below the water solubility cut-off presumably
have insufficient molecules in the aqueous phase to successfully
compete with water at hydrophilic modulation or transduction sites
on a receptor alter its function. Likewise, transitional compounds
and nonimmobilizers predicted by the Meyer-Overton correlation to
produce anesthesia either have lower than expected potency or lack
anesthetic efficacy altogether. And like NMDA cut-off hydrocarbons
in the present study, transitional compounds and nonimmobilizers
all share a common property of low aqueous solubility (Eger E I,
2nd. Mechanisms of Inhaled Anesthetic Action In: Eger E I, 2nd, ed.
The Pharmacology of Inhaled Anesthetics. Ill., USA: Baxter
Healthcare Corporation, 2002; 33-42). Nonimmobilizers such as
1,2-dichlorohexafluorocyclobutane fail to depress
GABA.sub.A-dependent pyramidal cells (Perouansky, et al., Anesth
Analg (2005) 100:1667-1673) or NMDA-dependent CA1 neurons (Taylor,
et al., Anesth Analg (1999) 89:1040-1045) in the hippocampus, and
likely lack these effects elsewhere in the central nervous system.
With decreasing water solubility, there is differential loss of
receptor effects--such as occurred with NMDA receptors versus
GABA.sub.A receptors in the present study. The anesthetic cut-off
effect in whole animal models correlates with agent water
solubility, and might be explained by the loss of one or more
anesthetic-receptor contributions to central nervous system
depression. Conversely, receptor molar water solubility cut-off
values may be used to define those ion channels that are sine qua
non for volatile anesthetic potency. Inhaled agents likely act via
low affinity interactions with multiple cell receptors and ion
channels to decrease neuronal excitability in the brain and spinal
cord, but a loss or inadequate contribution from certain
targets--perhaps GABA.sub.A or glycine receptors--as water
solubility decreases may render a drug a nonimmobilizer.
Additionally, agents having a water solubility below the cut-off
value for some anesthetic-sensitive receptors may also produce
undesirable pharmacologic properties, such as seizures following
the loss of GABA.sub.A receptor modulation (Raines, Anesthesiology
(1996) 84:663-671). In contrast, NMDA receptors can contribute to
immobilizing actions of conventional volatile anesthetics, 43 but
they are not as a general principle essential for inhaled
anesthetic action since an agent like pentane does not modulate
NMDA receptors--even at a saturated aqueous concentration (Table
3)--yet has a measurable minimum alveolar concentration (Liu, et
al., Anesth Analg (1993) 77:12-18; Taheri, et al., Anesth Analg
(1993) 77:7-11).
[0419] Although only water solubility was predictive of NMDA
receptor cut-off, size and shape nonetheless must be able influence
this effect. Most of the hydrocarbons examined in the present study
had functional groups located on the 1- or 2-carbon position.
However, the ethers were all 1,1'-oxybisalkanes; each member of the
ether consisted of symmetrical 1-carbon additions to alkyl groups
on either side of the oxygen atom (Table 2). Hence this
electron-rich oxygen atom allowing hydrogen bonding with water
molecules or amino acid residues with strong partial positive
charges lies buried in the middle of the ether. Consequently, for
hydrocarbons with equivalent molar water solubilities, it may be
more difficult for dialkyl ether to form hydrogen bonds in
hydrophilic receptor pockets compared to a long primary amine
(Table 2) that might more easily insert its nucleophilic terminus
into the anesthetic-binding pocket while the long hydrophobic
carbon chain remains in the lipid membrane. This may explain why
ethers in this study appear to exhibit an NMDA cut-off that is
slightly greater than hydrocarbons with other functional groups.
Perhaps if a methyl-alkyl ether series were used instead of a
dialkyl ether series, the apparent molar water solubility cut-off
for this group would have been lower.
[0420] As the hydrocarbon chain lengthened within any functional
group, the efficacy of GABA.sub.A receptor modulation also tended
to increase. This is consistent with the Meyer-Overton prediction
of increased anesthetic potency as a function of increasing
hydrophobicity (Mihic, et al., Mol Pharmacol (1994) 46:851-857;
Horishita, et al., Anesth Analg (2008) 107:1579-1586). However, the
efficacy by which NMDA receptors were inhibited by hydrocarbons
prior to the cut-off varied greatly between functional groups. Most
compounds caused about 25-to-40% inhibition of NMDA receptor
currents. However, the alkane n-butane almost completely inhibited
NMDA receptor currents prior to cut-off, whereas the thiol
1-pentanethiol caused only 15% NMDA receptor current inhibition.
Since solubility values are discontinuous within a hydrocarbon
series, it is not possible to evaluate changes in modulation
efficacy as solubility asymptotically approaches a cut-off within a
hydrocarbon functional group series. Perhaps agents that are closer
to the critical molar water solubility required for receptor
modulation begin to lose potency despite increasing drug
lipophilicity. If so, differences in NMDA receptor efficacy may
reflect the relative difference between this theoretical critical
molar water solubility and the aqueous solubility of the
pre-cut-off test agent.
[0421] Finally, discrete and distinct water solubility cut-off
values for anesthetic-sensitive receptors offer the possibility of
a structure-activity relationship that may aid new pharmaceutical
design. Anesthetics produce a number of desirable effects, such as
analgesia and amnesia, and a number of side effects, such as
hypotension and hypoventilation. Different pharmacodynamic
properties are likely mediated by different cell receptors or
channels or combinations thereof. Thus, by modifying a compound to
decrease its water solubility below the NMDA receptor cut-off,
absolute specificity for GABA.sub.A versus NMDA receptors may be
obtained and those side-effects mediated by NMDA receptor
inhibition should be reduced or eliminated. Conversely, highly
insoluble agents could be modified to increase the molar water
solubility above the NMDA cut-off in order to add desirable
pharmacologic effects from this receptor, provided that the
immobilizing versus NMDA receptor median effective concentrations
are not sufficiently different as to maintain relative receptor
specificity. At the same time, differential cut-off values suggest
an important limit to drug design. It will probably not be possible
to design an anesthetic with low-affinity receptor binding that
exhibits absolute specificity for NMDA receptors while having no
effect on GABA.sub.A receptors up to a saturating aqueous
concentration. Only if the minimum alveolar concentration and the
anesthetic potency at NMDA receptors are much greater than the
anesthetic potency at GABA.sub.A receptors might relative
anesthetic specificity for NMDA receptors be achieved.
Example 2
1,1,2,2,3,3,4-heptafluorocyclopentane (CAS#15290-77-4) Induces
Anesthesia
[0422] All known inhalation anesthetics modulate multiple unrelated
anesthetic receptors, such as transmembrane-3 (TM3) receptors,
transmembrane-4 (TM4) receptors, or both TM3 and TM4 receptors. We
tested a series of homologous n-alcohols, n-alkanes, n-alkenes,
n-alkynes, n-aldehydes, primary amines, 1-alkylfluorides, dialkyl
ethers, alkyl benzenes, esters, haloalkanes, ketones, sulfides, and
thiols that differed only by 1 or 2 carbon chain lengths. We
studied the effects of these drugs on NMDA receptors (a member of
the TM3 superfamily) and GABA.sub.A receptors (a member of the TM4
superfamily) at saturating drug concentrations in an oocyte
two-electrode voltage clamp model. For GABA.sub.A versus NMDA
receptors, we found that there is no correlation between
specificity and vapor pressure, carbon chain length, or molecular
volume. However, there exists a water solubility-specificity
cut-off value equal to about 1.1 mM with a 95% confidence interval
between about 0.4 and about 2.9 mM (calculated molar solubility in
water at pH=7). Compounds more soluble than this threshold value
can negatively modulate NMDA receptors and positively modulate
GABA.sub.A receptors. Compounds less soluble than this threshold
value only positively modulate GABA.sub.A receptors. We have also
identified approximate water solubility cut-off values for glycine
receptors, K2P channels, and voltage-gated sodium channels.
[0423] The above-described structure activity relationship was used
to identify candidate anesthetics, predict the receptor effect
profile of unknown candidate anesthetics, and provide the means by
which known anesthetics can be modified to change their water
solubility and thus their pharmacologic effect profile. Using the
above method, we have identified several candidate cyclic
halogenated hydrocarbon and cyclic halogenated heterocycles that
are predicted to modulate GABA.sub.A receptors, including agents
that show absolute selectivity for GABA.sub.A vs. NMDA receptors
(i.e., that potentiate GABA.sub.A receptors without inhibiting NMDA
receptors). We identified 1,1,2,2,3,3,4-heptafluorocyclopentane
(HFCP) (CAS#15290-77-4), and predicted by its solubility that it
would selectively modulate GABA.sub.A but not NMDA receptors and
exert a general anesthetic effect (it has until this time never
been evaluated in biological systems for narcotic effects). HFCP is
colorless, odorless, nonflammable, stable in soda lime, and has
sufficient vapor pressure to deliver via inhalation.
[0424] HFCP caused loss of righting reflex (a surrogate measure of
unconsciousness) in 4 healthy ND4 mice at 1.0.+-.0.2 (mean.+-.SD)
percent of 1 atmosphere. This odorless agent caused no excitement
or coughing during anesthetic induction. After 2 hours of
anesthesia, mice were awake after about 1 minute of discontinuing
HFCP administration. Histopathology of heart, lung, kidney and
liver tissues collected 2 days later revealed no evidence of
inflammation or toxicity. As predicted by its water solubility,
1,1,2,2,3,3,4-heptafluorocyclopentane potentiates GABA.sub.A,
glycine, and some inhibitory potassium channels in vitro, but has
no effect on NMDA receptors up to a saturating aqueous
concentration. Despite a lack of NMDA receptor effects,
1,1,2,2,3,3,4-heptafluorocyclopentane is able to produce the
desired pharmacologic endpoints of unconsciousness and immobility
that appears similar to desirable effects produced by conventional
agents.
[0425] To our knowledge, no new inhaled anesthetics are currently
under development because of an incomplete understanding of the
mechanisms of action and activity-structure relationships of these
agents. Inhalation anesthetics have among the lowest therapeutic
indices (low safety margin) of drugs in routine clinical use; there
is a need to develop newer and safer agents. We have identified a
physical property (molar water solubility) that is important to
determining whether an anesthetic can modulate channels or
receptors that contribute to immobility and amnesia. We have
applied this knowledge in order to identify a novel volatile
anesthetic of clinical use (HFCP) which also lacks NMDA receptor
modulation.
Example 3
1,1,2,2,3,3,4,5-octafluorocyclopentane (CAS#828-35-3) Induces
Anesthesia
[0426] 1,1,2,2,3,3,4,5-octafluorocyclopentane (CAS#828-35-3) caused
a loss of righting reflex in 4 healthy Sprague-Dawley rats at a
concentration of 3.3.+-.0.4 (mean.+-.SD) percent of 1 atmosphere.
This agent has a faint but pleasant odor and induced anesthesia
very rapidly without excitement or coughing. After discontinuing
the agent, rats were awake and ambulatory in less than 1 minute. As
predicted by its water solubility,
1,1,2,2,3,3,4,5-octafluorocyclopentane potentiates GABA.sub.A,
glycine, and some inhibitory potassium channels in vitro, but has
no effect on NMDA receptors up to a saturating aqueous
concentration. Despite a lack of NMDA receptor effects,
1,1,2,2,3,3,4,5-octafluorocyclopentane is able to produce the
desired pharmacologic endpoints of unconsciousness and immobility
that appears similar to desirable effects produced by conventional
agents.
Example 4
Perfluorotetrahydropyran (CAS#355-79-3) Induces Anesthesia
[0427] Perfluorotetrahydropyran (CAS#355-79-3) caused a loss of
righting reflex in mice at a concentration of 1-10%.
Example 5
2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-furan Induces
Anesthesia
[0428] 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-furan
(a mixture of the isomers from CAS#133618-59-4 and CAS#133618-49-2)
caused a loss of righting reflex in mice at a concentration of
1-10%.
Example 6
Synthesis Schemes
[0429] General schemes for the synthesis of the halogenated
anesthesia compounds described herein are known in the art.
References describing the synthesis schemes generally and for the
specific compounds are summarized in Table 4, below.
TABLE-US-00004 TABLE 4 Compound Published Reference GENERAL
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123768-18-3 Cyclopentane, 1,1,2,2,3,3- Stepanov, A. A.; Delyagina,
N. I.; Cherstkov, V. F. Russian Journal of hexafluoro- Organic
Chemistry (2010), 46(9), 1290-1295. Saku, Fuyuhiko; Takada,
Naokado; Inomura, Hideaki; Komata, Takeo. Jpn. Kokai Tokkyo Koho
(2000), JP 2000226346 A 20000815. Sekiya, Akira; Yamada, Toshirou;
Uruma, Takashi; Sugimoto, Tatsuya. PCT Int. Appl. (1998), WO
9851650 A1 19981119. Sekiya, Akira; Yamada, Toshiro; Watanabe,
Kazunori. Jpn. Kokai Tokkyo Koho (1996), JP 08143487 A 19960604.
Yamada, Toshiro; Mitsuda, Yasuhiro. PCT Int. Appl. (1994), WO
9407829 A1 19940414. Anton, Douglas Robert. PCT Int. Appl. (1991),
WO 9113846 A1 19910919. Bielefeldt, Dietmar; Braden, Rudolf;
Negele, Michael; Ziemann, Heinz. Eur. Pat. Appl. (1991), EP 442087
A1 19910821. Bielefeldt, Dietmar; Marhold, Albrecht; Negele,
Michael. Ger. Offen. (1989), DE 3735467 A1 19890503. 1259529-57-1
Cyclopentane, 1,1,2,2,3- pentafluoro- CYCLOHEXANES 830-15-9
Cyclohexane, Evans, D. E. M.; Feast, W. J.; Stephens, R.; Tatlow,
J. C. Journal of the 1,1,2,2,3,3,4,4-octafluoro- Chemical Society
(1963), (Oct.), 4828-34. FURANS 634191-25-6 Furan, 2,3,4,4-
tetrafluorotetrahydro-2,3- bis(trifluoromethyl)- 377-83-3 Furan,
2,2,3,3,4,4,5- Chepik, S. D.; Cherstkov, V. F.; Mysov, E. I.;
Aerov, A F.; Galakhov, M. heptafluorotetrahydro-5- V.; Sterlin, S.
R.; German, L. S. Izvestiya Akademii Nauk SSSR, Seriya
(trifluoromethyl)- Khimicheskaya(1991), (11), 2611-18. Abe,
Takashi; Nagase, Shunji. Journal of Fluorine Chemistry (1979),
13(6), 519-30. Abe, Takashi; Nagase, Shunji. Jpn. Kokai Tokkyo Koho
(1978), JP 53025552 A 19780309. Abe, Takashi; Nagase, Toshiharu;
Baba, Hajime. Jpn. Tokkyo Koho (1976), JP 51045594 B 19761204. Abe,
Takashi; Nagase, Shunji; Baba, Hajime. Jpn. Kokai Tokkyo Koho
(1976), JP 51082257 A 19760719. Abe, Takashi; Nagase, Shunji; Baba,
Hajime. Jpn. Kokai Tokkyo Koho (1975), JP 50106955 A 19750822. Abe,
Takashi; Nagase, Toshiharu; Baba, Hajime. Jpn. Tokkyo Koho (1973),
JP 48012742 B 19730423. 374-53-8 Furan, 2,2,3,3,4,5,5- Jpn. Kokai
Tokkyo Koho (1981), JP 56142877 A 19811107.
heptafluorotetrahydro-4- (trifluoromethyl)- Abe, Takashi; Nagase,
Shunji. Journal of Fluorine Chemistry (1979), 13(6), 519-30. Abe,
Takashi; Nagase, Shunji. Jpn. Kokai Tokkyo Koho (1978), JP 53124259
A 19781030. Abe, Takashi; Nagase, Shunji. Jpn. Kokai Tokkyo Koho
(1978), JP 53025552 A 19780309. Abe, Takashi; Nagase, Toshiharu;
Baba, Hajime. Jpn. Tokkyo Koho (1976), JP 51045594 B 19761204. Abe,
Takashi; Nagase, Shunji; Baba, Hajime. Jpn. Kokai Tokkyo Koho
(1976), JP 51082257 A 19760719. 133618-52-7 Furan, 2,2,3,4,5-
pentafluorotetrahydro-5- (trifluoromethyl)-, (2a,3a,4.beta.)-
133618-53-8 Furan, 2,2,3,4,5- Burdon, James; Coe, Paul L; Smith, J.
Anthony; Tatlow, John Colin. pentafluorotetrahydro-5- Journal of
Fluorine Chemistry (1991), 51(2), 179-96. (trifluoromethyl)-,
(2.alpha.,3.beta.,4.alpha.)- (9Cl) 133618-52-7 Furan, 2,2,3,4,5-
Burdon, James; Coe, Paul L.; Smith, J. Anthony; Tatlow, John Colin.
pentafluorotetrahydro-5- Journal of Fluorine Chemistry (1991),
51(2), 179-96. (trifluoromethyl)-, (2.alpha.,3.alpha.,4.beta.)-
(9Cl) 61340-70-3 Furan, 2,2,3,3,5,5- Abe, Takashi; Nagase, Shunji;
Baba, Hajime. Bulletin of the Chemical hexafluorotetrahydro-4-
Society of Japan (1976), 49(7), 1888-92. (trifluoromethyl)-
634191-26-7 Furan, 2,3- difluorotetrahydro-2,3-
bis(trifluoromethyl)- 1026470-51-8 Furan, 2-chloro- 2,3,3,4,4,5,5-
heptafluorotetrahydro- 179017-83-5 Furan, 2,2,3,3,4,4,5-
heptafluorotetrahydro-5- methyl- 133618-59-4 Furan, 2,2,3,3,4,5-
Burdon, James; Coe, Paul L.; Smith, J. Anthony; Tatlow, John Colin.
hexafluorotetrahydro-5- Journal of Fluorine Chemistry (1991),
51(2), 179-96. (trifluoromethyl)-, trans- (9Cl) 133618-49-2 Furan,
2,2,3,3,4,5- Burdon, James; Coe, Paul L.; Smith, J. Anthony;
Tatlow, John Colin. hexafluorotetrahydro-5- Journal of Fluorine
Chemistry (1991), 51(2), 179-96. (trifluoromethyl)-, cis- (9Cl)
PYRANS 71546-79-7 2H-Pyran, 2,2,3,3,4,5,5,6,6- Abe, Takashi;
Nagase, Shunji. Journal of Fluorine Chemistry (1979),
nonafluorotetrahydro-4- 13(6), 519-30. 356-47-8 2H-Pyran,
2,2,3,3,4,4,5,5,6- Abe, Takashi; Tamura, Masanori; Sekiya, Akira.
Journal of Fluorine nonafluorotetrahydro-6- Chemistry (2005),
126(3), 325-332. (trifluoromethyl)- Jpn. Kokai Tokkyo Koho (1980),
JP 55051084 A 19800414. Abe, Takashi; Nagase, Shunji. Journal of
Fluorine Chemistry (1979), 13(6), 519-30. Abe, Takashi; Kodaira,
Kazuo; Baba, Hajime; Nagase, Shunji. Journal of Fluorine Chemistry
(1978), 12(1), 1-25. No Inventor data available. (1961), GB 862538
19610315. Sander, Manfred; Helfrich, Frledrich; Blochl, Walter.
(1959), DE 1069639 19591126. No Inventor data available. (1954), GB
718318 19541110. 61340-74-7 2H-Pyran, 2,2,3,3,4,4,5,6,6- Abe,
Takashi; Nagase, Shunji. Journal of Fluorine Chemistry (1979),
nonafluorotetrahydro-5- 13(6), 519-30. (trifluoromethyl)- Abe,
Takashi; Nagase, Shunji; Baba, Hajime. Bulletin of the Chemical
Society of Japan (1976), 49(7), 1888-92. Abe, Takashi; Kodaira,
Kazuo; Baba, Hajime; Nagase, Shunji. Journal of Fluorine Chemistry
(1978), 12(1), 1-25. 657-48-7 2H-Pyran, 2,2,6,6- Wang, Chia-Lin J.
Organic Reactions (Hoboken, NJ, United States)
tetrafluorotetrahydro-4- (1985), 34, No pp. given.
(trifluoromethyl)- Dmowski, Wojciech; Kolinski, Ryszard A. Polish
Journal of Chemistry (1978), 52(1), 71-85. Hasek, W. R.; Smith, W.
C.; Engelhardt, V. A. Journal of the American Chemical Society
(1960), 82, 543-51. 874634-55-6 2H-Pyran, 2,2,3,3,4,4,5,5,6- Abe,
Takashi; Tamura, Masanori; Sekiya, Akira. Journal of Fluorine
nonafluorotetrahydro-6- Chemistry (2005), 126(3), 325-332. methyl-
355-79-3 Perfluorotetrahydropyran Wang, Chia-Lin J. Organic
Reactions (Hoboken, NJ, United States) (1985), 34, No pp. given.
Abe, Takashi; Tamura, Masanori; Sekiya, Akira. Journal of Fluorine
Chemistry (2005), 126(3), 325-332. Moldavsky, Dmitrii D.; Furin,
Georgii G. Journal of Fluorine Chemistry (1998), 87(1), 111-121.
Nishimura, Masakatsu; Shibuya, Masashi; Okada, Naoya; Tokunaga,
Shinji. Jpn. Kokai Tokkyo Koho (1989), JP 01249728 A 19891005.
Nishimura, Masakatsu; Okada, Naoya; Murata, Yasuo; Hirai, Yasuhiko.
Eur. Pat. Appl. (1988), EP 271272 A2 19880615. Abe, Takashi;
Nagase, Shunji. Journal of Fluorine Chemistry (1979), 13(6),
519-30. De Pasquale, Ralph J. Journal of Organic Chemistry (1973),
38(17), 3025-30. Abe, Takashi; Nagase, Toshiharu; Baba, Hajime.
Jpn. Tokkyo Koho (1973), JP 48012742 B 19730423.
Henne, Albert L; Richter, Sidney B. Journal of the American
Chemical Society (1952), 74, 5420-2. Kauck, Edward A.; Simons,
Joseph H. (1952), US 2594272 19520429. 362631-93-4 2H-Pyran,
2,2,3,3,4,5,5,6- octafluorotetrahydro-, (4R,6S)-rel- 65601-69-6
2H-Pyran,2,2,3,3,4,4,5,5,6- Zapevalova, T. B.; Plashkin, V. S.;
Selishchev, B. N.; Bil`dinov, K. N.; nonafluorotetrahydro-
Shcherbakova, M. S. Zhurnal Organicheskoi Khimii (1977), 13(12),
2573-4.
[0430] General schemes for the synthesis of halogenated compounds,
including the anesthesia compounds are provided, e.g., in Chambers,
"Fluorine in Organic Chemistry." WileyBlackwell, 2004.
ISBN:978-1405107877; Iskra, "Halogenated Heterocycles: Synthesis,
Application and Environment (Topics in Heterocyclic Chemistry)."
Springer, 2012. ISBN:978-3642251023; and Gakh, and Kirk,
"Fluorinated Heterocycles" (ACS Symposium Series). American
Chemical Society, 2009. ISBN:978-0841269538.
Halogenated Alcohols
[0431] Synthesis schemes for halogenated alcohols are summarized in
Table 4 and can be applied to the synthesis of the halogenated
alcohol anesthetic compounds described herein, including those of
Formula I. Illustrative references describing synthesis of
halogenated alcohols include without limitation, e.g., Mochalina,
et al., Akademii Nauk SSSR (1966), 169(6), 1346-9; Delyagina, et
al., Akademii Nauk SSSR, Seriya Khimicheskaya (1972), (2), 376-80;
Venturini, et al., Chimica Oggi (2008), 26(4), 36-38; Navarrini, et
al., Journal of Fluorine Chemistry (2008), 129(8), 680-685; Adcock,
et al., Journal of Fluorine Chemistry (1987), 37(3), 327-36;
Cantini, et al., Ital. Appl. (2007), IT 2007MI1481 A1 20071023;
Marraccini, et al., Eur. Pat. Appl. (1990), EP 404076 A1; Adcock,
et al., Journal of Organic Chemistry (1973), 38(20), 3617-18;
Aldrich, et al., Journal of Organic Chemistry (1964), 29(1), 11-15;
Weis, et al., Industrial & Engineering Chemistry Research
(2005), 44(23), 8883-8891; Arimura, et al., Journal of Chemical
Research, Synopses (1994), (5), 202-3; Du, et al., Journal of the
American Chemical Society (1990), 112(5), 1920-6; Galimberti, et
al., Journal of Fluorine Chemistry (2005), 126(11-12), 1578-1586;
and Navarrini, et al., Eur. Pat. Appl. (2004), EP 1462434 A1.
Generally, fluorinated alcohols can be synthesized using techniques
of direct hypofluorite addition and reverse hypofluorite addition,
described, e.g., in Navarrini, et al., Journal of Fluorine
Chemistry (2008), 129(8), 680-685.
[0432] In a typical direct hypofluorite addition, a stream of
hypofluorite is bubbled into a solution of an olefin maintained at
the desired temperature in a semi-batch method in order to operate
in excess of olefin. The addition reactor can be standard
dimensions designed 250 ml American Iron and Steel Institute (AISI)
316 stainless steel cooled by an external vessel. The reactor can
be realized with a discharge bottom valve and two feeding tubes.
The reactor's head can be equipped with: an outgoing tube for
collecting the off-gas stream and a mechanical/magnetic
transmission stirring system. The feed of the addition reactor and
the off-gases can be analysed on-line, e.g., via infrared (IR), gas
chromatography-thermal conductivity detector (GC-TCD) and gas
chromatography-infrared (GC-IR). At the end of the addition, the
reactor can be stripped with 4 nL/h of helium for about 30 min, the
vessel is unloaded and the resulting mixture analysed, e.g., via
gas chromatography (GC), GC-mass spectrometry (MS) e nuclear
magnetic resonance (NMR) .sup.19F. The raw reaction mixture can be
distilled in vacuum or at atmospheric pressure.
[0433] In a typical reverse hypofluorite addition, a stream of
olefin is bubbled into a solution of hypofluorite in order to
operate in excess of hypofluorite at the desired temperature. The
reaction can be carried out in a continuous stirred-tank reactor
(CSTR) with a continuous feed of both the reagents. The reactor is
charged with the solvent, cooled at the desired temperature and a
gaseous stream comprising CF.sub.3OF (2.35 nL/h), He (2.5 nL/h),
COF.sub.2 (0.3 nL/h) is fed in the reactor (e.g., for about 12 min)
before starting to add the olefin. After adding the olefin, for
safety reasons it is compulsory to eliminate the residual
hypofluorite before opening the reactor. In order to remove the
majority of the overloaded hypofluorite from the bulk, the liquid
phase can be stripped with a stream of 4 nL/h of helium for about
30 min at the temperature between -80 and -90.degree. C., after
that maintaining the temperature in the range -80 to -90.degree. C.
about 2 ml of CFCl.dbd.CFCl can be added in the reactor to
eliminate the remaining traces of hypofluorite. The traces of
CF.sub.3OF. react completely with CFCl.dbd.CFCl producing
CF.sub.3O--CFCl--CF.sub.2Cl.
Halogenated Cyclopentanes And Cyclohexanes
[0434] Synthesis schemes for halogenated cyclopentanes and
cyclohexanes are summarized in Table 4 and can be applied to the
synthesis of the halogenated cyclopentane and cyclohexane
anesthetic compounds described herein, including those of Formulae
V and VI. Illustrative references describing synthesis of
halogenated cyclopentanes and halogenated cyclohexanes include
without limitation, e.g., Imura, et al., Jpn. Kokai Tokkyo Koho
(2001), JP 2001261594A; Heitzman, et al., Journal of the Chemical
Society (1963), 281-9; Sekiya, Akira; et al., PCT Int. Publ. WO
96/00707 A1, Sekiya, et al., Jpn. Kokai Tokkyo Koho (1996), JP
08143487 A; Rao, et al, PCT Int. Publ. WO 93/05002 A2; Burdon, et
al., Journal of the Chemical Society (1965), (April), 2382-91;
Yamada, et al., Jpn. Kokai Tokkyo Koho (1999), JP 11292807 A;
Otsuki, Petrotech (Tokyo, Japan) (2005), 28(7), 489-493; Takada, et
al., Jpn. Kokai Tokkyo Koho (2002), JP 2002241325 A; Suzuki, et
al., Jpn. Kokai Tokkyo Koho (2001), JP 2001247494 A; Sekiya, et
al., Jpn. Kokai Tokkyo Koho (2001), JP 2001240567 A; Kim, et al.,
Jpn. Kokai Tokkyo Koho (2001), JP 2001240569 A; Sakyu, et al., Jpn.
Kokai Tokkyo Koho (2000), JP 2000247912 A; Saku, et al, Jpn. Kokai
Tokkyo Koho (2000), JP 2000226346 A; Yamada, et al., PCT Int. Publ.
WO 99/50209 A1; Yamada, et al., PCT Int. Publ. WO 99/33771 A1;
Sekiya, et al., PCT Int. Publ. WO 98/51650 A1; Banks, et al.,
Journal of the Chemical Society [Section] C: Organic (1968),
(5):548-50; Stepanov, et al., Russian Journal of Organic Chemistry
(2010), 46(9):1290-1295; Saku, et al., Jpn. Kokai Tokkyo Koho
(2000), JP 2000226346 A; Sekiya, et al., PCT Int. Publ. WO 98/51650
A1; Sekya, et al., Jpn. Kokai Tokkyo Koho (1996), JP 08143487 A;
Yamada, et al., PCT Int. Publ. WO 94/07829 A1; Anton, PCT Int.
Publ. WO 91/13846 A1; Bielefeldt, et al., Eur. Pat. Appl. (1991),
EP 442087 A1; Bielefeldt, et al., Ger. Offen. (1989), DE 3735467
A1; and Evans, et al., Journal of the Chemical Society (1963),
(October), 4828-34. Generally, fluorinated cyclopentanes and
fluorinated cyclohexanes can be synthesized using techniques
described, e.g., in Evans, et al., Journal of the Chemical Society
(1963), (October), 4828-34; Burdon, et al., Journal of the Chemical
Society (1965), (April), 2382-91.
[0435] A halogenated cyclopentane or halogenated cyclohexane can be
synthesized by reduction of a halogenated cycloalkene with lithium
aluminum hydride, as described, for example, by Evans, et al.,
Journal of the Chemical Society (1963), (October), 4828-34. In this
approach, a (poly)fluorocycloalkene is mixed with lithium aluminum
hydride in ether, producing several species of
(poly)fluorocycloalkenes in an addition-elimination process. These
(poly)fluorocycloalkenes can be characterized and several
(poly)fluorocycloalkanes and related compounds can be made from
them. Elimination is the most important reaction of such systems,
and a possible pathway for a cis-E2-process. For reaction of the
polyfluorocycloalkene with lithium aluminum anhydride, the
(poly)fluorocycloalkene is added dropwise to a stirred suspension
of lithium aluminum hydride in diethyl ether at -20.degree. C. When
the initial reaction subsides, the solution is refluxed, then
cooled to -20.degree. C. and 50% v/v sulphuric acid is added
dropwise, followed by water until no precipitate remained. The
dried (MgSO.sub.4) ethereal solution is evaporated through a vacuum
jacketed column (1'.times.11/2'') packed with glass helices to
leave a mixture of (poly)fluorocycloalkenes (180 g.) which is
separated by preparative gas chromatography (column type B,
100.degree. C., N.sub.2 flow-rate 60 l./hr.).
1H-Nonafluorocyclohexene prepared in this way contained a trace of
ether which can be removed by a second gas-chromatographic
separation in a column of type A packed with tritolyl
phosphate-kieselguhr (1:3). The double bond of the
(poly)fluorocycloalkenes can be readily saturated, e.g., by
fluorination with cobaltic fluoride, or by catalytic hydrogenation
at atmospheric pressure to produce the corresponding desired
(poly)fluorocycloalkane. Characterization of the
(poly)fluorocycloalkenes (poly)fluorocycloalkanes can be performed
using standard methodologies, including, e.g., oxidation, NMR
spectroscopy, mass spectroscopy, resistance to alkali, and gas
chromatography.
[0436] The vapour-phase fluorination of a cycloalkadiene with
cobaltic fluoride to produce the corresponding
(poly)fluorocycloalkane and the alternative synthesis of the
(poly)fluorocycloalkane starting from a (poly)fluorocycloalkene,
fluorinating with cobaltic fluoride and then reducing with lithium
aluminum hydride are described, for example, by Heitzman, et al.,
Journal of the Chemical Society (1963), 281-9. For vapour-phase
fluorination of a cycloalkadiene, the cycloalkadiene is fed into a
reactor containing cobalt trifluoride maintained at 190.degree.
C.-250.degree. C. The products are collected in a copper trap
cooled by solid carbon dioxide and any remaining in the reactor is
swept into the trap by a gentle stream of nitrogen. The total
product is poured into ice-water and washed with sodium hydrogen
carbonate solution. The clear organic layer is separated, and a
resin discarded. The combined products are distilled through a
vacuum-jacketed column (4'.times.1'') packed with Dixon gauze rings
( 1/16''.times. 1/16''). The distillation is controlled by
analytical gas chromatography. For synthesis of the
(poly)fluorocycloalkanes the corresponding
(poly)fluorocycloalkenes, the (poly)fluorocycloalkene is first
chlorinated and then reduced. For chlorination, the olefin and
liquid chlorine are irradiated with ultraviolet light for 4 hr. in
a quartz flask fitted with a condenser at -78.degree. C. The excess
of chlorine is removed by washing the products with aqueous sodium
hydrogen carbonate (10% w/v). The (poly)chlorofluorocycloalkane
product is dried (P.sub.2O.sub.5) and distilled, and can be
analyzed by gas chromatography and infrared spectroscopy. For
reduction, the (poly)chlorofluorocycloalkane product in dry ether
is added to a stirred suspension of lithium aluminum hydride in dry
ether at 0.degree. C. The apparatus is fitted with a condenser
cooled to -78.degree. C. After 5 hours' stirring at 15.degree. C.,
unchanged lithium aluminum hydride is destroyed at 0.degree. C. by
the careful addition of water followed by hydrochloric acid (10%
v/v) to dissolve the solid. The ethereal layer is distilled through
a column (2'.times.1/4'') and the residue can be analyzed by gas
chromatography and infrared spectroscopy.
[0437] The synthesis of (poly)fluorocycloalkanes by addition of
chlorine to the corresponding (poly)fluorocycloalkene, followed by
lithium aluminum hydride reduction is described, for example, by
Burdon, et al., Journal of the Chemical Society (1965), (April),
2382-91. For chlorination, the (poly)fluorocycloalkene is mixed
with an excess of chlorine in the presence of ultraviolet
irradiation. For reduction, the (poly)chlorofluorocycloalkane in
dry ether are added over 2 hr. to a stirred solution of lithium
aluminum hydride in dry ether at 0.degree. C. The reaction mixture
is stirred for a further 2 hr., and then the excess of lithium
aluminum hydride is destroyed in the usual way with 50% sulphuric
acid. Distillation of the dried (MgSO.sub.4) ether layer through a
6 in. column packed with glass helices leaves a residue. The
species in the residue can be separated by gas chromatography on a
preparative scale [e.g., column 4.8 m..times.35 mm. diam., packed
with dinonyl phthalate-kieselguhr (1:2); temp. 98.degree. C.
N.sub.2, flow-rate 11 l./hr.]. The eluted components can be
analyzed by infrared spectroscopy (IR) and/or NMR.
Halogenated Dioxanes
[0438] Synthesis schemes for halogenated dioxanes are summarized in
Table 4 and can be applied to the synthesis of the halogenated
dioxane anesthetic compounds described herein, including those of
Formula III. Illustrative references describing synthesis of
halogenated dioxanes include without limitation, e.g., Krespan, et
al., PCT Int. Appl. (1991), WO 91/04251; Krespan, et al., Journal
of Organic Chemistry (1991), 56(12), 3915-23; Coe, et al., Journal
of Fluorine Chemistry (1975), 6(2), 115-28; Burdon, et al., U.S.
Pat. No. 3,883,559; Burdon, et al., Tetrahedron (1971), 27(19),
4533-51; Adcock, et al., Journal of Fluorine Chemistry (1980),
16(3), 297-300; Dodman, et al., Journal of Fluorine Chemistry
(1976), 8(3), 263-74; Meinert, et al., Journal of Fluorine
Chemistry (1992), 59(3), 351-65; Berenblit, et al., Zhurnal
Prikladnoi Khimii (Sankt-Peterburg, Russian Federation) (1980),
53(4), 858-61; Lagow, et al., U.S. Pat. No. 4,113,435; Berenblit,
et al., Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian
Federation) (1975), 48(10), 2206-10; Adcock, et al., Journal of
Organic Chemistry (1975), 40(22), 3271-5; Abe, et al., Jpn. Tokkyo
Koho (1974), JP 49027588B; Berenblit, et al. Zhurnal Organicheskoi
Khimii (1974), 10(10), 2031-5; Adcock, et al., Journal of the
American Chemical Society (1974), 96(24), 7588; Abe, et al.,
Bulletin of the Chemical Society of Japan (1973), 46(8), 2524-7;
and Sianesi, et al., Ger. Offen. (1972), DE 2111696A. Generally,
fluorinated dioxanes can be synthesized by fluorinating dioxanes
over cobalt trifluoride (CoF.sub.3) or over potassium
tetrafluorocobaltate, for example, as described in Burdon, et al.,
Tetrahedron (1971), 27(19), 4533-51. Polyfluorodioxenes generally
can be synthesized by dehydrofluorination of the appropriate
polyfluorodioxane, for example, as described in Coe, et al.,
Journal of Fluorine Chemistry (1975), 6(2), 115-28.
[0439] In a typical fluorination of dioxane over CoF.sub.3, as
described, e.g., by Burdon, et al., Tetrahedron (1971), 27(19),
4533-51, dioxane is passed into a stirred bed of CoF.sub.3
(apparatus has been described in Bohme, Br. Dtsch. Chem. Ges.
74:248 (1941) and Bordwell, et al., J Amer Chem Soc 79:376 (1957)
at 100.degree. C. in a stream of N.sub.2 (10 dm.sup.3/hr). After
all the dioxane enters the reactor (about 3 hrs), the N.sub.2
stream is continued for a further 2 hr. The products are trapped at
-78.degree. C. and poured into iced water. Separation gives a pale
yellow liquid which deposits crystals of a tetrafluorodioxane on
being stored at -60.degree. C. The products from multiple (e.g.,
four) such fluorinations are washed with aqueous NaHCO.sub.3 and
distilled from P.sub.2O.sub.5 up a 2' vacuum jacketed glass column
packed with Dixon gauze rings ( 1/16''.times. 1/16''). The
fractions collected can be further separated, e.g., by analytical
gas-liquid chromatography (GLC) and analyzed, e.g., by GLC, IR, MS
and/or NMR.
[0440] In a typical fluorination of dioxane over KCoF.sub.4, as
described, e.g., by Burdon, et al., Tetrahedron (1971), 27(19),
4533-51, dioxane is passed in a stream of N.sub.2 (10 dm.sup.3/hr)
over a heated (230.degree. C.) and stirred bed of KCoF.sub.4 (the
apparatus has been described in Burdon, et al., J. Chem Soc. 2585
(1969)). The addition takes about 3 hr., and the N.sub.2 stream is
continued for 2 hr. afterwards. The products are collected in a
copper trap cooled to -78.degree. C.; washed with water and dried
to give crude material. The crude product, or a sample thereof, can
be further separated, e.g., by analytical gas-liquid chromatography
(GLC) and analyzed, e.g., by GLC, IR, MS and/or NMR.
[0441] In a typical isomerization of the polyfluorodioxanes over
AlF.sub.3, as described, e.g., by Burdon, et al., Tetrahedron
(1971), 27(19), 4533-51, dioxane is passed in a stream of N.sub.2
(1.5 dm.sup.3/hr) through a heated (temp stated in each case) glass
tube (12''.times.3/4'') packed with AlF.sub.3, powder supported on
glass chips. The products are collected in a trap cooled in liquid
air. The polyfluorodioxans are isomerized at elevated temperatures
in the range of about 390.degree. C. to about 490.degree. C. The
isomerized products can be further separated, e.g., by analytical
gas-liquid chromatography (GLC) and analyzed, e.g., by GLC, IR
and/or NMR.
Halogenated Dioxolanes
[0442] Synthesis schemes for halogenated dioxolanes are summarized
in Table 4 and can be applied to the synthesis of the halogenated
dioxolane anesthetic compounds described herein, including those of
Formula IV. Illustrative references describing synthesis of
halogenated dioxolanes include without limitation, e.g., Kawa, et
al., Jpn. Kokai Tokkyo Koho (2000), JP 2000143657A; Russo, et al.,
Eur. Pat. Appl. (1999), EP 937720 A1; Russo, et al., Journal of
Fluorine Chemistry (2004), 125(1), 73-78; Navarrini, et al.,
Journal of Fluorine Chemistry (1995), 71(1), 111-17; Navarrini, et
al., Eur. Pat. Appl. (1992), EP 499158A; Navarrini, et al., Eur.
Pat. Appl. (1995), EP 683181 A1; Muffler, et al., Journal of
Fluorine Chemistry (1982), 21(2), 107-32; Anton, et al., PCT Int.
Appl. (1991), WO 9109025 A2; Berenblit, et al., Zhurnal
Organicheskoi Khimii (1974), 10(10), 2031-5; Berenblit, et al.,
Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation)
(1975), 48(10), 2206-10; Prager, Journal of Organic Chemistry
(1966), 31(2), 392-4; Throckmorton, Journal of Organic Chemistry
(1969), 34(11), 3438-40; Sianesi, et al., Ger. Offen. (1972), DE
2111696 A; and Navarrini, et al., Eur. Pat. Appl. (1991),
EP460948A2. Generally, fluorinated dioxolanes can be synthesized by
addition of bis-(fluoroxy)difluoromethane (BDM) to halogenated
alkenes, e.g., as described by Navarrini, et al., J Fluorine Chem
71:111-117 (1995) or by reaction of chloroalkoxyfluorocarbonyl
halides or ketones with fluoride ions, e.g., as described by
Muffler, et al., J Fluorine Chem 21:107-132 (1982).
[0443] In a typical reaction for addition of
bis-(fluoroxy)difluoromethane (BDM) to halogenated alkenes, e.g.,
as described by Navarrini, et al., J Fluorine Chem 71:111-117
(1995), a semi-continuous or continuous system can be used. In a
general procedure for a semi-continuous system, a glass reactor
equipped with a mechanical stirrer, reflux condenser, thermocouple,
inner plunging pipes, maintained at temperatures in the range of
about -196.degree. C. to 25.degree. C. (see, Table 1 of Navarrini,
et al., supra) is charged with a 0.2-5 M solution (50-300 ml) of
the olefin in CFCl.sub.3, CF.sub.2Cl.sub.2 or with the pure olefin.
A flow of bis(fluoroxy)difluoromethane (usually about 1 liter per
hour flow rate) diluted with He in a 1:5 ratio is then fed into the
reactor until 90% of the olefin is converted. At the end of the
addition, helium is bubbled through the reaction mixture to remove
traces of unreacted CF.sub.2(OF).sub.2. The dioxolanes are isolated
via fractional distillation using an HMS 500 C Spaltrohr Fischer
apparatus. In a general procedure for a continuous system,
bis(fluoroxy)difluoromethane at a flow rate of about 0.4 liters per
hour diluted with He (about 2 liters per hour) and the olefin (36
mmol per hour) are simultaneously but separately fed, at the
temperatures in the range of about -196.degree. C. to 25.degree. C.
(see, Table 1 of Navarrini, et al., supra), into a multi-neck glass
reactor containing a 10.sup.-1 to 10.sup.-2 M solution of the
olefin and equipped with a magnetic entrainment mechanical stirrer,
reflux cooler, thermocouple and inner plunging pipes. After feeding
the reagents for 4 hr, helium is bubbled through the reaction
mixture to remove traces of unreacted CF.sub.2(OF).sub.2. The
reaction mixture can be purified by fractional distillation. The
reaction products can be separated through traps cooled to
-50.degree. C., -80.degree. C., -100.degree. C., -120.degree. C.
and -196.degree. C., as appropriate. Further distillation of the
mixtures collected at -100.degree. C. to -120.degree. C. through
traps cooled to -50.degree. C., -60.degree. C., -75.degree. C.,
-100.degree. C., -105.degree. C., -112.degree. C., -120.degree. C.
and -196.degree. C., respectively, allows collection of the pure
dioxolane, e.g., in the -75.degree. C., -100.degree. C.,
-112.degree. C. traps. The collected dioxolane product can be
analyzed, e.g., by GLC, IR, MS and/or NMR.
Halogenated Pyrans
[0444] Synthesis schemes for halogenated pyrans are summarized in
Table 4 and can be applied to the synthesis of the halogenated
tetrahydropyran anesthetic compounds described herein, including
those of Formula VII. Illustrative references describing synthesis
of halogenated pyrans include without limitation, e.g., Abe, et
al., Journal of Fluorine Chemistry (1979), 13(6), 519-30; Abe, et
al., Journal of Fluorine Chemistry (2005), 126(3), 325-332; Jpn.
Kokai Tokkyo Koho (1980), JP 55051084 A; Abe, et al., Journal of
Fluorine Chemistry (1979), 13(6), 519-30; Abe, et al., Journal of
Fluorine Chemistry (1978), 12(1), 1-25; GB Pat. No. 862538; Sander,
et al., (1959), DE 1069639; GB Pat No. 718318; Abe, et al., Journal
of Fluorine Chemistry (1979), 13(6), 519-30; Abe, et al., Bulletin
of the Chemical Society of Japan (1976), 49(7), 1888-92; Wang,
Organic Reactions (Hoboken, N.J., United States) (1985), vol. 34;
Dmowski, et al., Polish Journal of Chemistry (1978), 52(1), 71-85;
Hasek, et al., Journal of the American Chemical Society (1960), 82,
543-51; Abe, et al., Journal of Fluorine Chemistry (2005), 126(3),
325-332; Moldaysky, et al., Journal of Fluorine Chemistry (1998),
87(1), 111-121; Nishimura, et al., Jpn. Kokai Tokkyo Koho (1989),
JP 01249728 A; Nishimura, Eur. Pat. Appl. (1988), EP 271272 A2;
Abe, et al., Journal of Fluorine Chemistry (1979), 13(6), 519-30;
De Pasquale, Journal of Organic Chemistry (1973), 38(17), 3025-30;
Abe, et al., Jpn. Tokkyo Koho (1973), JP 48012742 B; Henne, et al.,
Journal of the American Chemical Society (1952), 74, 5420-2; Kauck,
et al., (1952), U.S. Pat. No. 2,594,272; and Zapevalova, et al.,
Zhurnal Organicheskoi Khimii (1977), 13(12), 2573-4. Generally,
fluorinated pyrans can be synthesized by reducing to a diol a
perfluorinated dibasic ester, cyclizing the diol to an ether,
chlorinating the cyclic ether to produce a perhalogenated cyclic
ether, and then fluorinating the perhalogenated cyclic ether to
produce the desired perfluorinated cyclic ether. Typically, for
reduction of a perfluorinated dibasic ester to a diol, the
perfluorinated dibasic ester is reduced with LiAlH.sub.4 in dry
ether to give the diol. The diol can be recrystallized, e.g., from
benzene. For cyclization, a mixture of the glycol and concentrated
sulfuric acid (10 g. or 0.1 mole) is kept in an oil bath at a
temperature in the range of about 185.degree. C. to about
250.degree. C. The cyclic ether which distilled over can be dried,
e.g., with Drierite, and redistilled. For chlorination of the
cyclic ether, the cyclic ether is placed in a quartz flask
illuminated with a sun lamp or UV lamp. Chlorine is bubbled through
for two days. An ice-cooled trap attached to the reflux condenser
caught entrained material, which is returned from time to time. For
fluorination of the cyclic ether to produce the perfluorinated
cyclic ether, the cyclic ether and SbF.sub.3Cl.sub.2 are heated at
155.degree. C. for 24 hours in a steel bomb. The pressure rises to
about 230 p.s.i. and drops to about 50 p.s.i. on cooling to room
temperature. This pressure is released into a Dry Ice trap which
collects raw perfluorinated cyclic ether. For larger rings, a
two-step procedure may be applied. The cyclic ether and
SbF.sub.3Cl.sub.2 are heated to 125.degree. C. for seven hours in a
450 ml. steel bomb, with shaking. The pressure rises to about 75
p.s.i. The temperature is raised to 160.degree. C. for 16 hours,
which raises pressure to 280 p.s.i. After cooling, a light fraction
is collected by distillation. The light fraction and
SbF.sub.3Cl.sub.2 are shaken at 160.degree. C. for five hours in a
bomb. The pressure rises to about 320 p.s.i. After cooling,
repeated distillation of the crude product gives the desired
perfluorinated cyclic ether. This perfluorinated cyclic ether can
be purified by passage through two 10% HCl bubblers to remove
traces of antimony salts, concentrated H.sub.2SO.sub.4 to remove
unsaturated impurities and finally distilled from P.sub.2O.sub.5.
The purified material can be analyzed, e.g., by GLC, IR, MS and/or
NMR.
Halogenated Furans
[0445] Synthesis schemes for halogenated furans are summarized in
Table 4 and can be applied to the synthesis of the halogenated
tetrahydrofuran anesthetic compounds described herein, including
those of Formula VI. Illustrative references describing synthesis
of halogenated furans include without limitation, e.g., Chepik, et
al., Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1991),
(11), 2611-18; Abe, et al., Journal of Fluorine Chemistry (1979),
13(6), 519-30; Abe, et al., Jpn. Kokai Tokkyo Koho (1978),
JP53025552A; Abe, et al., Jpn. Tokkyo Koho (1976), JP 51045594 B;
Abe, et al., Jpn. Kokai Tokkyo Koho (1976), JP 51082257 A; Abe, et
al., Jpn. Kokai Tokkyo Koho (1975), JP 50106955 A; Abe, et al.,
Jpn. Tokkyo Koho (1973), JP 48012742 B; Jpn. Kokai Tokkyo Koho
(1981), JP 56142877 A.; Abe, et al., Journal of Fluorine Chemistry
(1979), 13(6), 519-30; Abe, et al., Jpn. Kokai Tokkyo Koho (1978),
JP 53124259 A; Burdon, et al., Journal of Fluorine Chemistry
(1991), 51(2), 179-96; and Abe, et al., Bulletin of the Chemical
Society of Japan (1976), 49(7), 1888-92. Generally, fluorinated
furans can be produced, e.g., by electrochemical fluorination or by
exposure of a tetrahydrofuran to tetrafluorocobaltate(III) and/or
cobalt trifluoride.
[0446] A typical electrochemical fluorination reaction is
described, e.g., by Abe and Nagase, J Fluorine Chem 13:519-530
(1979). An electrolytic cell that can be used is described in Abe,
et al., J Fluorine Chem 12:1 (1978); and Abe, et al., J Fluorine
Chem 12:359 (1976). The compound (e.g., furan) to be fluorinated is
charged into the cell which contained 1 liter electrochemically
purified anhydrous hydrogen fluoride, and the resulting solution is
subjected to fluorination with an anodic current density of 3.5
A/dm.sup.2, a cell voltage of 5.0.about.6.2 V, and a cell
temperature of about 5-6.degree. C. over a period of 437 min (234
Ahr) until the cell voltage rose rapidly up to 9.0 V. Initially,
the products collected in cold traps (-196.degree. C.) are roughly
separated into at least two fractions using the traps of a
low-temperature distillation unit. After that, the composition of
products in these fractions can be can be further separated, e.g.,
by analytical gas-liquid chromatography (GLC) and analyzed, e.g.,
by GLC, IR, MS and/or NMR.
[0447] Typical reactions for fluorination by
tetrafluorocobaltate(III) and/or cobalt trifluoride are described,
e.g., in Burdon, et al., Journal of Fluorine Chemistry (1991),
51(2), 179-96. For fluorination by Potassium
Tetrafluorocobaltate(III) a tetrahydrofuran is passed through a
standard stirred reactor (1.2m.times.15 cm i.d.; 6 Kg KCoF.sub.4)
at 200.degree. C., during 3 hours. The reactor is purged with
nitrogen (15 liters per hour for 1.5 h), and the trap contents are
washed with water. The dried crude product can be analyzed, e.g.,
by GLC, IR, MS and/or NMR. For fluorination by cobalt trifluoride,
crude product is passed via a liquid seal into a similar reactor
(1.3m.times.18 cm i.d.; packed with 10 Kg of CoF.sub.3) during 3 h.
Temperatures are maintained in the range of about 120-150.degree.
C. Following a nitrogen sweep (25 liters per hour for 2 h) the
contents of the cold trap (-78.degree. C.) are poured onto ice and
washed with water. The combined products are washed (aqueous sodium
bicarbonate then water) and dried (MgSO.sub.4 then P.sub.2O.sub.5).
A part can be fractionally distilled through a 1 m vacuum jacketed
spinning band column, with analysis by GLC. Fractions obtained can
be further separated by preparative GLC (e.g., Pye Series 104
machine, with a flame-ionization detector; tube packings, Ucon L.B.
550.times. on Chromasorb P 30-60 (1:4); analysis tube, 1.7m.times.4
mm i.d.; semi-preparative tube, 9.1 m.times.7 mm i.d.) to give a
pure sample of each product. As appropriate or desired, the
fluorinated products can be isomerized. The apparatus used for
isomerization can be an electrically-heated hard glass tube (320
mm.times.25 mm i.d.), packed with a 1:1 mixture of aluminium
fluoride and small glass spheres. Before use, this is heated to
280.degree. C. for 24 h, whilst a slow stream of nitrogen is passed
through. With the tube temperature at 420.degree. C., the
fluorinated product is passed through during 30 min. in a stream of
nitrogen. Isomerized and non-isomerized products can be further
separated, e.g., by analytical gas-liquid chromatography (GLC) and
analyzed, e.g., by GLC, IR, MS and/or NMR.
[0448] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
* * * * *