U.S. patent application number 12/692365 was filed with the patent office on 2010-05-13 for neurogenesis by muscarinic receptor modulation.
This patent application is currently assigned to BrainCells, Inc.. Invention is credited to Carrolee Barlow, Alex Broadhead, Todd A. Carter, Dana Gitnick, Kym I. Lorrain, Andrew Morse, Jammieson C. Pires, Kai Treuner.
Application Number | 20100120842 12/692365 |
Document ID | / |
Family ID | 37591836 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100120842 |
Kind Code |
A1 |
Barlow; Carrolee ; et
al. |
May 13, 2010 |
NEUROGENESIS BY MUSCARINIC RECEPTOR MODULATION
Abstract
The instant disclosure describes methods for treating diseases
and conditions of the central and peripheral nervous system by
stimulating or increasing neurogenesis. The disclosure includes
compositions and methods based on muscarinic receptor modulation,
such as via inhibition of acetylcholine esterase (AChE) activity,
alone or in combination with another neurogenic agent to stimulate
or activate the formation of new nerve cells.
Inventors: |
Barlow; Carrolee; (Del Mar,
CA) ; Carter; Todd A.; (San Diego, CA) ;
Lorrain; Kym I.; (San Diego, CA) ; Pires; Jammieson
C.; (San Diego, CA) ; Morse; Andrew; (San
Diego, CA) ; Gitnick; Dana; (San Marcos, CA) ;
Treuner; Kai; (San Diego, CA) ; Broadhead; Alex;
(San Diego, CA) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
BrainCells, Inc.
San Diego
CA
|
Family ID: |
37591836 |
Appl. No.: |
12/692365 |
Filed: |
January 22, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11467527 |
Aug 25, 2006 |
7678363 |
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12692365 |
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60711846 |
Aug 26, 2005 |
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60727127 |
Oct 14, 2005 |
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60738133 |
Nov 17, 2005 |
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60803826 |
Jun 2, 2006 |
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Current U.S.
Class: |
514/305 |
Current CPC
Class: |
A61K 31/325 20130101;
A61K 31/445 20130101; A61P 25/36 20180101; A61P 25/28 20180101;
A61P 25/08 20180101; A61P 25/32 20180101; A61K 45/06 20130101; A61K
31/403 20130101; A61P 25/20 20180101; A61K 31/473 20130101; A61P
25/30 20180101; A61K 31/55 20130101; A61K 31/00 20130101; A61P
25/24 20180101; A61K 31/4745 20130101; A61P 25/22 20180101; A61P
25/00 20180101; A61P 27/02 20180101; A61P 43/00 20180101; A61K
31/66 20130101; A61P 25/18 20180101; A61K 31/403 20130101; A61K
2300/00 20130101; A61K 31/445 20130101; A61K 2300/00 20130101; A61K
31/473 20130101; A61K 2300/00 20130101; A61K 31/4745 20130101; A61K
2300/00 20130101; A61K 31/55 20130101; A61K 2300/00 20130101; A61K
31/66 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/305 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61P 25/22 20060101 A61P025/22; A61P 25/18 20060101
A61P025/18 |
Claims
1. A method of treating a nervous system disorder related to a
psychiatric condition, in a subject or patient in need thereof,
said method comprising administering a composition consisting
essentially of sabcomeline and an S SRI, wherein the composition is
effective to treat the disorder.
2. The method of claim 1, wherein said psychiatric condition is
anxiety.
3. The method of claim 1, wherein the SSRI is fluoxetine.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] Under 35 U.S.C. .sctn.120 this application is a divisional
application of U.S. application Ser. No. 11/467,527, filed Aug. 25,
2006, now pending, which claims benefit of priority under 35 U.S.C.
.sctn.119(e) to U.S. Provisional Patent Applications 60/711,846,
filed Aug. 26, 2005; 60/727,127, filed Oct. 14, 2005; 60/738,133,
filed Nov. 17, 2005; and 60/803,826, filed Jun. 2, 2006; all of
which are hereby incorporated by reference as if fully set
forth.
FIELD OF THE DISCLOSURE
[0002] The instant disclosure relates to methods for treating
diseases and conditions of the central and peripheral nervous
system by stimulating or increasing neurogenesis via modulation of
muscarinic receptor activity, including via inhibition of
acetylcholine esterase (AChE) activity in combination with another
neurogenic agent. The disclosure includes methods based on the
application of a neurogenesis modulating agent having activity
against muscarinic receptors and/or an AChE inhibitor with another
neurogenic agent to stimulate or activate the formation of new
nerve cells.
BACKGROUND OF THE DISCLOSURE
[0003] Neurogenesis is a vital process in the brains of animals and
humans, whereby new nerve cells are continuously generated
throughout the life span of the organism. The newly born cells are
able to differentiate into functional cells of the central nervous
system and integrate into existing neural circuits in the brain.
Neurogenesis is known to persist throughout adulthood in two
regions of the mammalian brain: the subventricular zone (SVZ) of
the lateral ventricles and the dentate gyrus of the hippocampus. In
these regions, multipotent neural progenitor cells (NPCs) continue
to divide and give rise to new functional neurons and glial cells
(for review Gage 2000). It has been shown that a variety of factors
can stimulate adult hippocampal neurogenesis, e.g., adrenalectomy,
voluntary exercise, enriched environment, hippocampus dependent
learning and anti-depressants (Yehuda 1989, van Praag 1999, Brown J
2003, Gould 1999, Malberg 2000, Santarelli 2003). Other factors,
such as adrenal hormones, stress, age and drugs of abuse negatively
influence neurogenesis (Cameron 1994, McEwen 1999, Kuhn 1996, Eisch
2004).
[0004] Muscarinic cholinergic receptors mediate the effects of the
neurotransmitter acetylcholine in the central and peripheral
nervous systems. In the CNS, muscarinic receptors play a central
role in mediating cognitive function and are abundant in the
forebrain, including the dentate gyrus of the hippocampus and the
cerebral cortex. In the PNS, muscarinic receptors mediate
parasympathetic activity. Muscarinic receptors are also involved in
mediating the actions of acetylcholine on certain organs that are
responsive to parasympathetic cholinergic stimulation; for example,
they affect the contractibility of smooth muscle in the
gastrointestinal tract, the secretion of gastric acid, the force
and rate of heart muscle contraction, the secretory activity of
exocrine glands that receive parasympathetic innervation, such as
the salivary glands, and the constriction of bronchial tissue.
[0005] Five sub-types of muscarinic receptors have been
characterized, and are designated m1, m2, m3, m4, and m5. m1
receptors are found in the CNS and peripheral ganglia, m2 receptors
are found on cardiac cells and in the brainstem, m3 receptors are
found in smooth muscle, endocrine (e.g., the pancreas) and exocrine
glands (e.g., the lacrimal glands), and the cerebral cortex, m4
receptors are found primarily in the neostriatum, and m5 receptors
are found primarily in the substantia nigra. Muscarinic receptors
are G-protein coupled receptors (GPCRs), with the activity of the
m1, m3 and m5 receptors mediated by the phosphoinositide
second-messenger system, and the m2 and m4 receptors linked to the
adenylate cyclase second messenger system.
[0006] Compounds with activity against muscarinic receptors have
been studied for the treatment of conditions linked to cholinergic
dysfunction, such as Alzheimer's Disease, which is associated with
the degeneration of cholinergic neurons in the forebrain. Clinical
testing has revealed a high degree of debilitating, dose-limiting
side effects associated with compounds active against the m2 and m3
receptor subtypes, including cardiovascular and gastrointestinal
side effects. In contrast, compounds that are selective for m1
receptors, or m1 and m4 receptors have generally been found to have
better clinical profiles, with enhanced efficacy and decreased side
effects. To date, there is has been little research regarding the
use of muscarinic compounds to treat diseases not characterized by
or substantially resulting from cholinergic dysfunction.
[0007] Acetylcholinesterase, or AChE, is also known as erythrocyte
(or RBC) cholinesterase and acetylcholine acetylhydrolase. It is
classified at EC 3.1.1.7 and is found in various locations,
including the blood and neural synapses. AChE catalyzes hydrolysis
of the neurotransmitter acetylcholine into choline and acetic acid
where acetylcholine is a pan-muscarinic and pan-nicotinic receptor
ligand. The hydrolysis reaction reaction permits an activated
cholinergic neuron to return to a resting state.
[0008] Citation of the above documents is not intended as an
admission that any of the foregoing is pertinent prior art. All
statements as to the date or representation as to the contents of
these documents is based on the information available to the
applicant and does not constitute any admission as to the
correctness of the dates or contents of these documents.
BRIEF SUMMARY OF THE DISCLOSURE
[0009] Disclosed herein are compositions and methods for the
prophylaxis and treatment of diseases, conditions and injuries of
the central and peripheral nervous systems by modulating
neurogenesis, including stimulating or increasing the generation of
neurons. Aspects of the methods, and activities of the
compositions, include modulating neurogenesis in cases of a
disease, disorder, or condition of the nervous system. Embodiments
of the disclosure include methods of treating a neurodegenerative
disorder, neurological trauma including brain or central nervous
system trauma and/or recovery therefrom, depression, anxiety,
psychosis, learning and memory disorders, and ischemia of the
central and/or peripheral nervous systems.
[0010] In one aspect, methods of modulating, such as by stimulating
or increasing, neurogenesis are disclosed. The neurogenesis may be
at the level of a cell or tissue. The cell or tissue may be present
in an animal subject or a human being, or alternatively be in an in
vitro or ex vivo setting. In some embodiments, neurogenesis is
stimulated or increased in a neural cell or tissue, such as that of
the central or peripheral nervous system of an animal or human
being. In cases of an animal or human, the methods may be practiced
in connection with one or more disease, disorder, or condition of
the nervous system as present in the animal or human subject. Thus,
embodiments disclosed herein include methods of treating a disease,
disorder, or condition by administering at least one neurogenesis
modulating agent having activity against muscarinic receptors
(hereinafter referred to as a "muscarinic agent"). The muscarinic
agent may be used alone or in combination with one or more
additional neurogenic agents.
[0011] While a muscarinic agent may be considered a "direct" agent
in that it has direct activity against a muscarinic receptor by
interactions therewith, the disclosure includes a muscarinic agent
that may be considered an "indirect" agent in that it does not
directly interact with a muscarinic receptor. Thus, an indirect
agent acts on a muscarinic receptor indirectly, or via production,
generation, stability, or retention of an intermediate agent which
directly interacts with a muscarinic receptor. In other
embodiments, an indirect agent may be one that increases the amount
of choline or available choline, such as by increasing choline
synthesis as a non-limiting example.
[0012] In some embodiments, an indirect agent is an inhibitor of
AChE activity. Like a direct muscarinic agent, an indirect agent
may be used alone or in combination with one or more additional
neurogenic agents, as described herein. An AChE inhibitor may be a
cholinergic agonist, such as an inhibitor that suppresses the
enzymatic activity of AChE. In some embodiments, an AChE inhibitor
binds an AChE active site.
[0013] An additional neurogenic agent as described herein may be
another direct muscarinic agent, another indirect muscarinic agent
(such as AChE inhibitor), or a neurogenic agent that does not act,
directly or indirectly, through a muscarinic receptor. Thus in some
embodiments, an additional neurogenic agent is one that acts,
directly or indirectly, through a mechanism other than a muscarinic
receptor.
[0014] In one aspect, methods of modulating, such as by stimulating
or increasing, neurogenesis are disclosed. The neurogenesis may be
at the level of a cell or tissue. The cell or tissue may be present
in an animal subject or a human being, or alternatively be in an in
vitro or ex vivo setting. In some embodiments, neurogenesis is
stimulated or increased in a neural cell or tissue, such as that of
the central or peripheral nervous system of an animal or human
being. In cases of an animal or human, the methods may be practiced
in connection with one or more disease, disorder, or condition of
the nervous system as present in the animal or human subject. Thus,
embodiments disclosed herein include methods of treating a disease,
disorder, or condition by administering a muscarinic agent alone or
in combination with another neurogenic agent, as described herein.
The additional neurogenic agent may be another muscarinic agent
(direct or indirect) or a neurogenic agent that acts through a
mechanism independent from a muscarinic receptor.
[0015] In another aspect, methods of using chemical entities as
muscarinic agents to modulate, such as by increasing, neurogenesis
are disclosed. In some embodiments, a chemical entity used as a
muscarinic agent is a therapeutically or pharmaceutically
acceptable reversible AChE inhibitor. Alternatively, an acceptable
irreversible AChE inhibitor may also be used in some embodiments of
the disclosure. Additional embodiments comprise an inhibitor that
is a tertiary amine which crosses the blood brain barrier.
[0016] Non-limiting examples of AChE inhibitors as a muscarinic
agent include an organophosphate (such as metrifonate or
echothiophate), an aminoacridine (such as tacrine), a carbamate
(such as physostigmine or neostigmine or rivastigmine) a
phenanthrine derivative (such as galantamine), or a piperidine
derivative (such as donepezil) that has neurogenic activity. In
other embodiments, a carbamate, such as a quaternary amine (and
pyridostigmine, ambenonium and demarcarium as non-limiting
examples) are disclosed for use in the practice of the invention.
Other non-limiting examples of an AChE inhibitor with neurogenic
activity include itopride, (-)-huperzine A, and phenserine. A yet
additional embodiment of an AChE inhibitor is edrophonium.
[0017] Embodiments described herein include a combination of more
than one of the muscarinic agents disclosed herein or known to the
skilled person. Of course a neurogenic muscarinic agent may be
used, either alone or in combination with one or more additional
muscarinic agents or other neurogenic agents. Compositions
disclosed herein include such combinations of muscarinic agents,
including AChE inhibitor(s) as a non-limiting embodiment, and other
neurogenic agent(s).
[0018] In another aspect, the disclosed methods include identifying
a patient suffering from one or more diseases, disorders, or
conditions, or a symptom thereof, and administering to the patient
a muscarinic agent, alone or in combination with another neurogenic
agent, as described herein. In some embodiments, a method including
identification of a subject as in need of an increase in
neurogenesis, and administering to the subject one or more
muscarinic agents is disclosed herein. In other embodiments, the
subject is a patient, such as a human patient.
[0019] Additional embodiments describe a method including
administering a muscarinic agent, alone or in combination with
another neurogenic agent, to a subject exhibiting the effects of
insufficient amounts of, or inadequate levels of, neurogenesis. In
some embodiments, the subject may be one that has been subjected to
an agent that decreases or inhibits neurogenesis. Non-limiting
examples of an inhibitor of neurogenesis include opioid receptor
agonists, such as a mu receptor subtype agonist like morphine In a
related manner, a method provides for administering a muscarinic
agent, alone or in combination with another neurogenic agent, to a
subject or person that will be subjected to an agent that decreases
or inhibits neurogenesis. Non-limiting embodiments include those
where the subject or person is about to be administered morphine or
another opioid receptor agonist, like another opiate, and so about
to be subject to a decrease or inhibition of neurogenesis.
Non-limiting examples include administering a muscarinic agent,
alone or in combination with another neurogenic agent, to a subject
before, simultaneously with, or after the subject is administered
morphine or other opiate in connection with a surgical
procedure.
[0020] Also disclosed are methods for preparing a population of
neural stem cells suitable for transplantation, comprising
culturing a population of neural stem cells (NSCs) in vitro, and
contacting the cultured neural stem cells with at least one
muscarinic agent, optionally in combination with another muscarinic
agent, such as an AChE inhibitor, and/or another neurogenic agent.
In some embodiments, the stem cells are prepared and then
transferred to a recipient host animal or human. Non-limiting
examples of preparation include 1) contact with a muscarinic agent,
optionally in combination with another muscarinic agent, such as an
AChE inhibitor, and/or another neurogenic agent, until the cells
have undergone neurogenesis, such as that which is detectable by
visual inspection or cell counting, or 2) contact with a muscarinic
agent, such as an AChE inhibitor, optionally in combination with
another muscarinic agent and/or another neurogenic agent, until the
cells have been sufficiently stimulated or induced toward or into
neurogenesis. The cells prepared in such a non-limiting manner may
be transplanted to a subject, optionally with simultaneous, nearly
simultaneous, or subsequent administration of a neurogenic agent,
or a muscarinic agent, such as an AChE inhibitor, to the subject.
While the neural stem cells may be in the form of an in vitro
culture or cell line, in other embodiments, the cells may be part
of a tissue which is subsequently transplanted into a subject.
[0021] In yet another aspect, the disclosure includes methods of
modulating, such as by stimulating or increasing, neurogenesis in a
subject by administering a muscarinic agent, optionally in
combination with another muscarinic agent, such as an AChE
inhibitor, and/or another neurogenic agent. In some embodiments,
the neurogenesis occurs in combination with the stimulation of
angiogenesis which provides new cells with access to the
circulatory system.
[0022] The details of additional embodiments are set forth in the
accompanying drawings and the description below. Other features,
objects, and advantages of the embodiments will be apparent from
the drawings and detailed description, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a dose-response curve showing effect of the
muscarinic agent sabcomeline on neuronal differentiation. Data is
presented as the percentage of the neuronal positive control, with
basal media values subtracted. EC.sub.50 was observed at a
sabcomeline concentration of 8.04-82 M, compared to 5.28 .mu.M for
the positive control.
[0024] FIG. 2 is a dose-response curve showing effect of the
muscarinic agent sabcomeline on astrocyte differentiation. Data is
presented as the percentage of the astrocyte positive control, with
basal media values subtracted. Sabcomeline was found to have no
effect on astrocyte differentiation,
[0025] FIG. 3 is a dose-response curve measuring the
toxicity/trophism effect of the muscarinic agent sabcomeline on a
population of cultured neural stem cells. Data is presented as the
percentage of the basal media cell count. Toxic doses produce
viability values below 80% of the basal media control, while
trophic compounds show a dose-dependent increase in cell count.
Sabcomeline has no detectable toxicity, and shows a significant
trophic effect.
[0026] FIG. 4 shows the effect of various concentrations of the
muscarinic agent sabcomeline on neurogenesis of human neural stem
cells (hNSC) in neurosphere culture (diamonds: 1 .mu.M sabcomeline;
squares: 10 .mu.M sabcomeline; triangles: 30 .mu.M sabcomeline, X:
positive control (basal media with known proliferative agent);
asterisk: negative control (basal media). Neurogenesis is measured
as the total area of a single neurosphere comprising human neural
stem cells as a function of time. Results are presented as the
percent increase in area over basal media. Sabcomeline enhanced
proliferation and/or survival of hNSC compared to basal media at
all time periods tested.
[0027] FIG. 5 is a series of immunofluorescent microscopic images
of monolayers of human neural stem cells (hNSC) after
immunohistochemistry staining with the neuronal marker TUJ-1
(blue), the astrocyte marker GFAP (red), and a nuclear cell marker
(Hoechst 33342) (example 5). The upper left image is a negative
control (basal media), the upper middle image is a neuronal
positive control (basal media plus a known promoter of neuronal
differentiation), and the upper right image is an astrocyte
positive control (basal media plus a known promoter of astrocyte
differentiation). The lower image shows the effect of sabcomeline
on hNSC differentiation.
[0028] FIG. 6 shows the effect of chronic dosing with sabcomeline
on the locomotor activity of rats (squares: 0.01 mg/kg; triangles:
0.05 mg/kg; diamonds: negative control (vehicle)). Sabcomeline had
no significant effect on locomotor activity. "mpk" stands for
mg/kg.
[0029] FIG. 7 shows the effect of chronic dosing with sabcomeline
on the body weight of rats (squares: 0.01 mg/kg; triangles: 0.05
mg/kg; diamonds: negative control (vehicle)). Sabcomeline had no
significant effect on body weight.
[0030] FIG. 8 shows the effect of acute dosing with sabcomeline on
the performance of rats in the modified forced swim test (dark
grey: 0.01 mg/kg; white: 0.05 mg/kg; light grey: negative control
(vehicle). Sabcomeline had no significant effects on performance in
the swim test.
[0031] FIG. 9 shows the effect of chronic dosing of rats with
sabcomeline on latency to eat in a novelty-suppressed feeding assay
(left: vehicle; middle: 0.01 mg/kg; right: 0.05 mg/kg). Sabcomeline
decreased the latency to eat in a dose-dependent manner, with a
statistically significant decrease at 0.05 mg/kg.
[0032] FIG. 10 shows the effect of chronic dosing of rats with
sabcomeline on cognitive performance in a novel object recognition
assay (left: vehicle; middle: 0.01 mg/kg; right: 0.05 mg/kg).
Sabcomeline significantly enhanced performance in the assay at 0.01
mg/kg.
[0033] FIG. 11 shows the effect of acute dosing of rats (injection
once daily for five days) with sabcomeline on neural cell
proliferation within the dentate gyrus (left: vehicle; middle: 0.01
mg/kg; right: 0.05 mg/kg). Results are presented as the mean number
of Brdu-positive cells per cubic mm. A dose-related increase in
proliferation was observed.
[0034] FIG. 12 shows the effect of chronic dosing of rats with
Sabcomeline on the differentiation of neural progenitor cells into
mature neuron within the subgranular zone of the dentate gyrus.
Chronic Sabcomeline treatment resulted in a 20 and 18 percent
increase at 0.01 and 0.05 mg/kg/day, respectively.
[0035] FIG. 13A shows the effect of chronic dosing of rats with
sabcomeline, fluoxetine, or a combination of both agents in the
novelty suppressed feeding depression model (gray: vehicle; white:
5.0 mg/kg fluoxetine; hatched: 0.01 mg/kg sabcomeline;
cross-hatched: 5.0 mg/kg Fluoxetine and 0.01 mg/kg sabcomeline).
The combination of fluoxetine with sabcomeline resulted in
significantly enhanced performance in the assay relative to vehicle
or either agent alone.
[0036] FIG. 13B shows the effect of acute dosing of rats (injection
once daily for five days) with sabcomeline, fluoxetine, or a
combination of both agents on neural cell proliferation within the
dentate gyrus (gray: vehicle; white: 5.0 mg/kg fluoxetine; hatched:
0.01 mg/kg sabcomeline; cross-hatched: 5.0 mg/kg Fluoxetine and
0.01 mg/kg sabcomeline) in the dorsal hippocampus and the ventral
hippocampus. Results are presented as the mean number of
Brdu-positive cells per cubic mm. The combination of sabcomeline
and fluoxetine resulted in a significant increase in proliferation
indicating increased neurogenesis.
[0037] FIG. 14 is a dose-response curve showing effects of the
neurogenic agents donepezil (acetylcholinesterase inhibitor) and
captopril (angiotensin converting enzyme inhibitor) in combination
on neuronal differentiation compared to the effect of either agent
alone. When run independently, each compound was tested in a
concentration response curve ranging from 0.01 .mu.M to 31.6 .mu.M.
In combination, the compounds were combined at equal concentrations
at each point (for example, the first point in the combined curve
consisted of a test of 0.01 .mu.M donepezil and 0.01 .mu.M
captopril). Data is presented as the percentage of the neuronal
positive control, with basal media values subtracted. When used
alone, EC.sub.50 was observed at a donepezil concentration of 4.7
.mu.M or a captopril concentration of 2.0 .mu.M in test cells. When
used in combination neurogenesis is greatly enhanced: EC.sub.50 was
observed at a combination of donepezil and captopril at
concentrations of 0.24 .mu.M each.
[0038] FIG. 15 is a dose-response curve showing the reduction of
astrocyte differentiation by buspirone (a 5-HT1a agonist) in
combination with donepezil (an acetylcholinesterase inhibitor).
When run alone, buspirone potently induces astrocyte
differentiation with an EC.sub.50 of 5.7 .mu.M at a maximum of 60%
of the positive control. The addition of donepezil results in
significant inhibition of astrocyte differentiation to a maximum of
14% positive control with an estimated EC.sub.50 greater than 31.6
.mu.M.
DETAILED DESCRIPTION OF MODES OF PRACTICE
[0039] "Neurogenesis" is defined herein as proliferation,
differentiation, migration and/or survival of a neural cell in vivo
or in vitro. In various embodiments, the neural cell is an adult,
fetal, or embryonic neural stem cell or population of cells. The
cells may be located in the central nervous system or elsewhere in
an animal or human being. The cells may also be in a tissue, such
as neural tissue. In some embodiments, the neural cell is an adult,
fetal, or embryonic progenitor cell or population of cells, or a
population of cells comprising a mixture of stem cells and
progenitor cells. Neural cells include all brain stem cells, all
brain progenitor cells, and all brain precursor cells. Neurogenesis
includes neurogenesis as it occurs during normal development, as
well as neural regeneration that occurs following disease, damage
or therapeutic intervention, such as by the treatment described
herein.
[0040] A "neurogenic agent" is defined as a chemical agent or
reagent that can promote, stimulate, or otherwise increase the
amount or degree or nature of neurogenesis in vivo or ex vivo or in
vitro relative to the amount, degree, or nature of neurogenesis in
the absence of the agent or reagent. In some embodiments, treatment
with a neurogenic agent increases neurogenesis if it promotes
neurogenesis by at least about 5%, at least about 10%, at least
about 25%, at least about 50%, at least about 100%, at least about
500%, or more in comparison to the amount, degree, and/or nature of
neurogenesis in the absence of the agent, under the conditions of
the method used to detect or determine neurogenesis. As described
herein, a muscarinic agent, such as an AChE inhibitor, that
promotes, stimulates, or otherwise increases the amount or degree
or nature of neurogenesis is a neurogenic agent.
[0041] The term "astrogenic" is defined in relation to
"astrogenesis" which refers to the activation, proliferation,
differentiation, migration and/or survival of an astrocytic cell in
vivo or in vitro. Non-limiting examples of astrocytic cells include
astrocytes, activated microglial cells, astrocyte precursors and
potentiated cells, and astrocyte progenitor and derived cells. In
some embodiments, the astrocyte is an adult, fetal, or embryonic
astrocyte or population of astrocytes. The astrocytes may be
located in the central nervous system or elsewhere in an animal or
human being. The astrocytes may also be in a tissue, such as neural
tissue. In some embodiments, the astrocyte is an adult, fetal, or
embryonic progenitor cell or population of cells, or a population
of cells comprising a mixture of stem and/or progenitor cells, that
is/are capable of developing into astrocytes. Astrogenesis includes
the proliferation and/or differentiation of astrocytes as it occurs
during normal development, as well as astrogenesis that occurs
following disease, damage or therapeutic intervention.
[0042] The term "stem cell" (or neural stem cell (NSC)), as used
herein, refers to an undifferentiated cell that is capable of
self-renewal and differentiation into neurons, astrocytes, and/or
oligodendrocytes.
[0043] The term "progenitor cell" (e.g., neural progenitor cell),
as used herein, refers to a cell derived from a stem cell that is
not itself a stem cell. Some progenitor cells can produce progeny
that are capable of differentiating into more than one cell
type.
[0044] The term "muscarinic agent" as used herein includes a
neurogenic agent, as defined herein, that elicits an observable
response upon contacting a muscarinic receptor. "Muscarinic agents"
useful in the methods described herein include compounds or agents
that, under certain conditions, may act as: agonists (i.e., agents
able to elicit one or more biological responses of a muscarinic
receptor); partial agonists (i.e., agents able to elicit one or
more biological responses of a receptor to a less than maximal
extent, e.g., as defined by the response of the receptor to an
agonist); antagonists (agents able to inhibit one or more
characteristic responses of a muscarinic receptor, for example, by
competitively or non-competitively binding to the muscarinic
receptor, a ligand of the receptor, and/or a downstream signaling
molecule); and/or inverse agonists (agents able to block or inhibit
a constitutive activity of a muscarinic receptor) of one or more
subtypes of muscarinic receptors. For example, the muscarinic agent
alvameline, described in more detail below, is known to have
agonist properties with respect to m.sub.1 receptors and antagonist
properties with respect to m.sub.2 and/or m.sub.3 receptors under
certain conditions.
[0045] In some embodiments, the muscarinic agent(s) used in the
methods described herein has "selective" activity under certain
conditions against one or more muscarinic receptor subtypes with
respect to the degree and/or nature of activity against one or more
other muscarinic receptor subtypes. For example, in some
embodiments, the muscarinic agent has an agonist effect against one
or more subtypes, and a much weaker effect or substantially no
effect against other subtypes. As another example, a muscarinic
agent used in the methods described herein may act as an agonist at
one or more muscarinic receptor subtypes and as antagonist at one
or more other muscarinic receptor subtypes. In some embodiments,
muscarinic agents have activity against m.sub.1 muscarinic
receptors, while having substantially lesser activity against one
or more other muscarinic receptor subtypes. In certain embodiments,
selective activity of one or more muscarinic agonists results in
enhanced efficacy, fewer side effects, lower effective dosages,
less frequent dosing, or other desirable attributes.
[0046] In some embodiments, the muscarinic agent(s) used in the
methods described herein are substantially inactive with respect to
other receptors (i.e., non-muscarinic receptors), such as 5-HT
receptors, dopamine receptors, epinephrine receptors, histamine
receptors, glutamate receptors, and the like. However, in some
embodiments, muscarinic agent(s) are active against one or more
additional receptor subtypes.
[0047] In other embodiments, a muscarinic agent as used herein
includes a neurogenesis modulating agent, as defined herein, that
elicits an observable neurogenic response by producing, generating,
stabilizing, or increasing the retention of an intermediate agent
which, when contacted with a muscarinic receptor, results in the
neurogenic response. As used herein, "increasing the retention of
or variants of that phrase or the term "retention" refer to
decreasing the degradation of, or increasing the stability of, an
intermediate agent. As a non-limiting example, and where
acetylcholine is the intermediate agent, an AChE inhibitor
increases the retention of acetylcholine by decreasing its
degradation by AChE.
[0048] An "AChE inhibitor" is a ligand that binds AChE and has
(acetylcholine, or ACh, receptor stimulating) activity. An AChE
inhibitor may be a cholinergic agonist or otherwise contribute to
cholinergic tone by allowing more ACh to be present to stimulate
receptor activity. In some embodiments, an AChE inhibitor may act
by inhibiting AChE enzymatic activity.
[0049] In some embodiments, an AChE inhibitor or cholinergic
agonist stimulates ACh receptor activity by an increase of at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 30%, at least about 50%, at least about 75%, at
least about 100%, at least about 200%, at least about 300%, at
least about 400%, or at least about 500% or more than the amount of
receptor activity in the absence of the AChE inhibitor. AChE
inhibitors that lack ACh receptor antagonist may be advantageously
used in the disclosed.
[0050] The disclosed embodiments include methods of modulating,
such as by increasing, neurogenesis by contacting one or more
neural cells with a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent. The amount of a muscarinic agent, such as
an AChE inhibitor, optionally in combination with another
muscarinic agent and/or another neurogenic agent, may be selected
to be effective to produce an improvement in a treated subject, or
detectable neurogenesis in vitro. In some embodiments, the amount
is one that also minimizes clinical side effects seen with
administration of the inhibitor to a subject. The amount of a
muscarinic agent, such as an AChE inhibitor, used in vivo may be
about 50%, about 45%, about 40%, about 35%, about 30%, about 25%,
about 20%, about 18%, about 16%, about 14%, about 12%, about 10%,
about 8%, about 6%, about 4%, about 2%, or about 1% or less of the
maximum tolerated dose for a subject, such as where another
muscarinic agent and/or another neurogenic agent is used in
combination. This is readily determined for each muscarinic agent
that has been in clinical use or testing, such as in humans.
[0051] In some cases, where an amount or concentration of a
muscarinic agent, optionally in combination with another neurogenic
agent, results in an undesirable level of astrogenic activity, the
invention includes methods of using a muscarinic agent at a
sub-astrogenic amount or concentration so as to reduce or avoid the
inhibition of beneficial neurogenesis induced by the agent. In some
embodiments, the sub-astrogenic amount of a muscarinic agent is
used in combination with an amount of a neurogenic sensitizing
agent, such as one which has no detectable or measurable astrogenic
activity. As a non-limiting example, a subject in need of the
combination is administered a sub-astrogenic amount of a muscarinic
agent and an amount of a neurogenic sensitizing agent.
[0052] A sub-astrogenic amount or concentration of a muscarinic
agent is an effective one which does not induce an unacceptable
level or degree of astrogenesis. A sub-astrogenic amount is thus
less than the maximum level of astrogenesis that can be induced or
stimulated by a chemical agent. In some embodiments, the
sub-astrogenic amount may range from a partially astrogenic amount
of a muscarinic agent to an amount wherein no measurable or
detectable level of astrogenesis occurs in an assay like those
described herein.
[0053] Non-limiting examples of sub-astrogenic levels include
amounts which decrease the level of astrogenesis, relative to the
amount of the muscarinic agent that produces the highest levels of
astrogenesis in vitro, or the maximum tolerated amount in vivo, by
at least about 5%, at least about 10%, at least about 25%, at least
about 50%, at least about 70%, at least about 75%, at least about
80%, at least about 82%, at least about 84%, at least about 86%, at
least about 88%, at least about 90%, at least about 92%, at least
about 94%, at least about 96%, at least about 98%, or at least
about 99%. The use of a reduced amount of muscarinic agent may also
decrease the level of neurogenic activity provided by the
agent.
[0054] The sub-astrogenic amount of a muscarinic agent may be an
amount that also potentiates or sensitizes, such as by activating
or inducing cells to proliferate and/or differentiate, a population
of neural cells for neurogenesis when the amount of agent is used
in combination with a neurogenic sensitizing agent. The degree of
potentiation or sensitization for neurogenesis may be determined
with use of the combination in any appropriate neurogenesis assay,
including, but not limited to, the neuronal differentiation assay
described herein. In some embodiments, the amount of muscarinic
agent is the highest amount which produces no detectable
neurogenesis in vitro but yet produces neurogenesis, or a
measurable shift in efficacy in promoting neurogenesis in vitro,
when used in combination with a neurogenic sensitizing agent. In
other embodiments, the amount used in vivo may be about 50%, about
45%, about 40%, about 35%, about 30%, about 25%, about 20%, about
18%, about 16%, about 14%, about 12%, about 10%, about 8%, about
6%, about 4%, about 2%, or about 1% or less of the maximum
tolerated dose for a subject. Non-limiting examples of subjects
include both human beings and animals in assays for behavior linked
to neurogenesis. Exemplary animal assays include those described
herein.
[0055] Furthermore, the sub-astrogenic amount may also be an amount
that decreases or minimizes clinical side effects seen with
administration of a muscarinic agent in a subject. Non-limiting
examples of such side effects include headache, nervousness, light
headedness, nausea, excitement, dizziness, sweating/clamminess,
insomnia, vertigo, somnolence, and stomach upset.
[0056] The amount of a neurogenic sensitizing agent may be an
amount selected to be effective to produce an improvement in a
treated subject, or detectable neurogenesis in vitro, when used in
combination with a muscarinic agent. In some embodiments, such as
in the case of known neurogenic agents, the amount is one that
minimizes clinical side effects seen with administration of the
agent to a subject. The amount of neurogenic sensitizing agent used
in vivo may be about 50%, about 45%, about 40%, about 35%, about
30%, about 25%, about 20%, about 18%, about 16%, about 14%, about
12%, about 10%, about 8%, about 6%, about 4%, about 2%, or about 1%
or less of the maximum tolerated dose for a subject. This is
readily determined for each neurogenic sensitizing agent that has
been in clinical use or testing, such as in humans
[0057] In other embodiments, the amount of neurogenic sensitizing
agent is the highest amount which produces no detectable
neurogenesis in vitro, including in animal (or non-human) models
for behavior linked to neurogenesis, but yet produces neurogenesis,
or a measurable shift in efficacy in promoting neurogenesis in the
in vitro assay, when used in combination with a muscarinic agent.
Alternative embodiments include amounts which produce about 1%,
about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about
14%, about 16%, about 18%, about 20%, about 25%, about 30%, about
35%, or about 40% or more of the neurogenesis seen with the amount
that produces the highest level of neurogenesis in an in vitro
assay.
[0058] In another aspect, the disclosed embodiments include methods
of using a muscarinic agent, such as an AChE inhibitor, optionally
in combination with another muscarinic agent and/or another
neurogenic agent, at a level at which neurogenesis occurs. The
amount of a muscarinic agent, such as an AChE inhibitor, optionally
in combination with another muscarinic agent and/or another
neurogenic agent, may be any that is effective to produce
neurogenesis, optionally with reduced or minimized amounts of
astrogenesis. In some embodiments, the amount may be the lowest
needed to produce a desired, or minimum, level of detectable
neurogenesis or beneficial effect.
[0059] In methods of increasing neurogenesis by contacting cells
with a muscarinic agent, such as an AChE inhibitor, optionally in
combination with another muscarinic agent and/or another neurogenic
agent, the cells may be in vitro or in vivo. In some embodiments,
the cells are present in a tissue or organ of a subject animal or
human being. In embodiments featuring use of an AChE inhibitor, it
may be any that has ACh receptor stimulating activity, such as a
cholinergic agonist, as described herein.
[0060] The cells are those capable of neurogenesis, such as to
result, whether by direct differentiation or by proliferation and
differentiation, in differentiated neuronal or glial cells.
Representative, and non-limiting examples of non-muscarinic agents,
such as non-AChE inhibitor, neurogenic agents for use in the
disclosed embodiments are provided below.
[0061] In applications to an animal or human being, the embodiments
relate to a method of bringing cells into contact with a muscarinic
agent, such as an AChE inhibitor, optionally in combination with
another muscarinic agent and/or another neurogenic agent, in
effective amounts to result in an increase in neurogenesis in
comparison to the absence of the muscarinic agent or combination. A
non-limiting example is in the administration of the muscarinic
agent to the animal or human being. Such contacting or
administration may also be described as exogenously supplying the
muscarinic agent to a cell or tissue.
[0062] In some embodiments, the term "animal" or "animal subject"
refers to a non-human mammal, such as a primate, canine, or feline.
In other embodiments, the terms refer to an animal that is
domesticated (e.g. livestock) or otherwise subject to human care
and/or maintenance (e.g. zoo animals and other animals for
exhibition). In other non-limiting examples, the terms refer to
ruminants or carnivores, such as dogs, cats, birds, horses, cattle,
sheep, goats, marine animals and mammals, penguins, deer, elk, and
foxes.
[0063] The disclosed embodiments also relate to methods of treating
diseases, disorders, and conditions of the central and/or
peripheral nervous systems (CNS and PNS, respectively) by
administering a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent. As used herein, "treating" includes
prevention, amelioration, alleviation, and/or elimination of the
disease, disorder, or condition being treated or one or more
symptoms of the disease, disorder, or condition being treated, as
well as improvement in the overall well being of a patient, as
measured by objective and/or subjective criteria. In some
embodiments, treating is used for reversing, attenuating,
minimizing, suppressing, or halting undesirable or deleterious
effects of, or effects from the progression of, a disease,
disorder, or condition of the central and/or peripheral nervous
systems. In other embodiments, the method of treating may be
advantageously used in cases where additional neurogenesis would
replace, replenish, or increase the numbers of cells lost due to
injury or disease as non-limiting examples.
[0064] The amount of a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent, may be any that results in a measurable
relief of a disease condition like those described herein. As a
non-limiting example, an improvement in the Hamilton depression
scale (HAM-D) score for depression may be used to determine (such
as quantitatively) or detect (such as qualitatively) a measurable
level of improvement in the depression of a subject.
[0065] Non-limiting examples of symptoms that may be treated with
the methods described herein include abnormal behavior, abnormal
movement, hyperactivity, hallucinations, acute delusions,
combativeness, hostility, negativism, withdrawal, seclusion, memory
defects, sensory defects, cognitive defects, and tension.
Non-limiting examples of abnormal behavior include irritability,
poor impulse control, distractibility, and aggressiveness.
[0066] In some embodiments, the muscarinic agonist is milameline
(CI-979), or a compound that is structurally or functionally
related to milameline. Structures, biological activity data,
methods for obtaining biological activity data, methods of
synthesis, modes of administration and pharmaceutical formulations
for milameline and related compounds are disclosed in U.S. Pat.
Nos. 4,786,648, 5,362,860, 5,424,301, 5,650,174, 4,710,508,
5,314,901, 5,356,914, and 5,356,912, all of which are herein
incorporated by reference in their entirety.
[0067] In other embodiments, the muscarinic agonist is xanomeline,
or a compound that is structurally or functionally related to
xanomeline. Structures, biological activity data, methods for
obtaining biological activity data, methods of synthesis, modes of
administration and pharmaceutical formulations for xanomeline and
related compounds are disclosed in U.S. Pat. Nos. 5,041,455,
5,043,345, and 5,260,314, all of which are herein incorporated by
reference in their entirety.
[0068] In further embodiments, the muscarinic agent is alvameline
(LU 25-109), or a compound that is functionally or structurally
related to alvameline. Structures, biological activity data,
methods for obtaining biological activity data, methods of
synthesis, modes of administration and pharmaceutical formulations
for alvameline and related compounds are disclosed in U.S. Pat.
Nos. 6,297,262, 4,866,077, RE36,374, 4,925,858, PCT Publication No.
WO 97/17074, and in Moltzen et al., J Med Chem. 1994 Nov. 25;
37(24):4085-99, all of which are herein incorporated by reference
in their entirety.
[0069] In additional embodiments, the muscarinic agent is
2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (YM-796) or
YM-954, or a functionally or structurally related compound.
Structures, biological activity data, methods for obtaining
biological activity data, methods of synthesis, modes of
administration and pharmaceutical formulations for YM-796, YM-954,
and related compounds are disclosed in U.S. Pat. Nos. 4,940,795,
RE34,653, 4,996,210, 5,041,549, 5,403,931, and 5,412,096, and in
Wanibuchi et al., Eur. J. Pharmacol., 187, 479-486 (1990), all of
which are herein incorporated by reference in their entirety.
[0070] In yet further embodiments, the muscarinic agent is
cevimeline (AF102B) or a compound that is functionally or
structurally related to cevimeline. Cevimeline is approved by the
FDA for the treatment of symptoms of dry mouth in patients with
Sjorgren's Syndrome. Structures, biological activity data, methods
for obtaining biological activity data, methods of synthesis, modes
of administration and pharmaceutical formulations for cevimeline
and related compounds are disclosed in U.S. Pat. Nos. 4,855,290,
5,340,821, 5,580,880 (American Home Products), and U.S. Pat. No.
4,981,858 (optical isomers of AF102B), all of which are herein
incorporated by reference in their entirety.
[0071] In yet additional embodiments, the muscarinic agent is
sabcomeline (SB 202026), or a compound that is functionally or
structurally related to sabcomeline. Structures, biological
activity data, methods for obtaining biological activity data,
methods of synthesis, modes of administration and pharmaceutical
formulations for sabcomeline and related compounds are described in
U.S. Pat. Nos. 5,278,170, RE35,593, 6,468,560, 5,773,619,
5,808,075, 5,545,740, 5,534,522, and 6,596,869, U.S. Patent
Publication Nos. 2002/0127271, 2003/0129246, 2002/0150618,
2001/0018074, 2003/0157169, and 2001/0003588, Bromidge et al., J
Med Chem, 19;40(26):4265-80 (1997), and Harries et al., British J.
Pharm., 124, 409-415 (1998), all of which are herein incorporated
by reference in their entirety. As shown in FIGS. 1-5 and 11,
sabcomeline significantly enhances the proliferation, growth, and
survival of human NSCs, and preferentially stimulates NSCs to
differentiate along a neuronal lineage. Moreover, as shown in FIGS.
9-10, sabcomeline significantly enhances neurogenesis, reduces
depressive and anxious behaviors and enhances cognitive function in
vivo.
[0072] Sabcomeline, alone or in combination with one or more agents
as described herein, is specifically contemplated for use in the
methods and compositions as disclosed herein.
[0073] In other embodiments, the muscarinic agent is talsaclidine
(WAL 2014 FU), or a compound that is functionally or structurally
related to talsaclidine. Structures, biological activity data,
methods for obtaining biological activity data, methods of
synthesis, modes of administration and pharmaceutical formulations
for talsaclidine and related compounds are disclosed in U.S. Pat.
Nos. 5,451,587, 5,286,864, 5,508,405, 5,451,587, 5,286,864,
5,508,405, and 5,137,895, and in Pharmacol. Toxicol., 78, 59-68
(1996), all of which are herein incorporated by reference in their
entirety.
[0074] In some embodiments, the muscarinic agent is a
1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivative,
such as
tetra(ethyleneglycol)(4-methoxy-1,2,5-thiadiazol-3-yl)[3-(1-methyl-1,2,5,-
6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl]ether, or a compound
that is functionally or structurally related to a
1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivative.
Structures, biological activity data, methods for obtaining
biological activity data, methods of synthesis, and other
information relating to using these derivatives and related
compounds as pharmaceutical agents is provided by Cao et al.
("Synthesis and biological characterization of
1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as
muscarinic agonists for the treatment of neurological disorders."
J. Med. Chem. 46(20):4273-4286, 2003), which is herein incorporated
by reference in its entirety.
[0075] In further embodiments, the muscarinic agent is
besipiridine, SR-46559, L-689,660, S-9977-2, AF-102, or
thiopilocarpine. The structures, biological activity data, methods
for obtaining biological activity data, methods of synthesis, modes
of administration and pharmaceutical formulations for these and
related compounds are known in the art and/or described in the
publications referenced herein.
[0076] In yet further embodiments, the muscarinic agent is an
analog of clozapine or a pharmaceutically acceptable salt, ester,
amide, or prodrug form thereof. In some embodiments, the analog is
a diaryl[a,d]cycloheptene, such as an amino substituted form
thereof. A compound that is functionally or structurally related to
such analogs of clozapine may also be used in the practice of the
invention. In some embodiments, the compound is
N-desmethylclozapine, which has been reported to be a metabolite of
clozapine and discovered to be highly neurogenic in assays as
disclosed herein. Structures, biological activity data, methods for
obtaining biological activity data, methods of synthesis, modes of
administration and pharmaceutical formulations for these analogs
and related compounds are disclosed in US 2005/0192268 and WO
05/63254, both of which are hereby incorporated by reference as if
fully set forth.
[0077] In other embodiments, the muscarinic agent is an m.sub.1
receptor agonist selected from 55-LH-3B, 55-LH-25A, 55-LH-30B,
55-LH-4-1A, 40-LH-67, 55-LH-15A, 55-LH-16B, 55-LH-11C, 55-LH-31A,
55-LH-46, 55-LH-47, 55-LH-4-3A, or a compound that is functionally
or structurally related to one or more of these agonists.
Structures, biological activity data, methods for obtaining
biological activity data, methods of synthesis, modes of
administration and pharmaceutical formulations for these agonists
and related compounds are disclosed in US 2005/0130961 and WO
04/087158, both of which are hereby incorporated by reference as if
fully set forth.
[0078] In additional embodiments, the muscarinic agent is a
benzimidazolidinone derivative or a compound that is functionally
or structurally related to a benzimidazolidinone derivative. The
derivative or related compound may be selective for the m.sub.1
and/or m.sub.4 receptor subtypes. Structures, biological activity
data, methods for obtaining biological activity data, methods of
synthesis, modes of administration and pharmaceutical formulations
for these derivatives and related compounds are disclosed in U.S.
Pat. No. 6,951,849, US 2003/0100545, WO 04/089942, and WO
03/028650, all of which are hereby incorporated by reference as if
fully set forth.
[0079] In yet additional embodiments, the muscarinic agent is a
spiroazacyclic compound or a compound that is functionally or
structurally related to a spiroazacyclic compound. In some
embodiments, the compound is 1-oxa-3,8-diaza-spiro[4,5]decan-2-one.
Structures, biological activity data, methods for obtaining
biological activity data, methods of synthesis, modes of
administration and pharmaceutical formulations for these
spiroazacyclic compounds and related compounds are disclosed in
U.S. Pat. No. 6,911,452 and WO 03/057698, both of which are hereby
incorporated by reference as if fully set forth.
[0080] In other embodiments, the muscarinic agent is a
tetrahydroquinoline analog or a compound that is functionally or
structurally related to a tetrahydroquinoline analog. Structures,
biological activity data, methods for obtaining biological activity
data, methods of synthesis, modes of administration and
pharmaceutical formulations for these spiroazacyclic compounds and
related compounds are disclosed in US 2003/0176418, US
2005/0209226, and WO 03/057672, all of which are hereby
incorporated by reference as if fully set forth.
[0081] In further embodiments, the agent is a muscarinic agonist or
a compound that is functionally or structurally related to such an
agonist. Structures, biological activity data, methods for
obtaining biological activity data, methods of synthesis, modes of
administration and pharmaceutical formulations for these agonists
and related compounds are disclosed in U.S. Pat. No. 6,627,645, US
2005/0113357, and WO 01/83472, all of which are hereby incorporated
by reference as if fully set forth.
[0082] In yet further embodiments, the agent is a muscarinic
agonist or a compound that is functionally or structurally related
to such an agonist. Structures, biological activity data, methods
for obtaining biological activity data, methods of synthesis, modes
of administration and pharmaceutical formulations for these
agonists and related compounds are disclosed in U.S. Pat. No.
6,528,529, US 2003/0144285, WO 01/05763, and WO 99/50247, all of
which are hereby incorporated by reference as if fully set
forth.
[0083] Structures, biological activity data, methods for obtaining
biological activity data, methods of synthesis, modes of
administration and pharmaceutical formulations for other muscarinic
agents are described in U.S. Pat. Nos., 5,675,007, 5,902,814,
6,051,581, 5,384,408, 5,468,875, 5,773,458, 5,512,574, 5,407,938,
5,668,174, 4,870,081, 4,968,691, 4,971,975, 5,110,828, 5,166,357,
5,124,460, 5,132,316, 5,262,427, 5,324,724, 5,534,520, 5,541,194,
5,599,937, 5,852,029, 5,981,545, 5,527,813, 5,571,826, 5,574,043,
5,578,602, 5,605,908, 5,641,791, 5,646,289, 5,665,745, 5,672,709,
6,911,477, 5,834,458, 5,756,501, 5,510,478, 5,093,333, 5,571,819,
4,992,457, and 5,362,739, Intl. Publication Nos. EP 384288, WO
9917771, JP 61280497, WO 9700894, WO 9847900, WO 9314089, EP
805153, WO 9422861, WO 9603377, EP 429344, EP 647642, WO 9626196,
WO 9800412, WO 9531457, JP 61280497, JP 6298732, JP 6305967, WO
9640687, EP 311313, EP 370415, EP 709381, EP 723781, EP 727208, EP
727209, WO 9740044 and EP 384285, Ward et al., J. Med. Chem., 38,
3469 (1995), Wermuth et al., Farmaco., 48(2):253-74 (1993), Biorg.
Med. Chem. Let., 2; 833-838 (1992), and Nordvall et al., J. Med.
Chem., 35, 1541 (1992), all of which are herein incorporated by
reference in their entirety.
[0084] As provided herein, an AChE inhibitor may be an
organophosphate such as metrifonate or echothiophate as
non-limiting examples.
[0085] Metrifonate (also known as metriphonate or trichlorfon) or
its active metabolite, 2,2-dimethyldichlorovinyl phosphate (or
dichlorvos or DDVP). Metrifonate is represented by the following
formula:
(CH.sub.3O).sub.2--PO--CHOH--OCl.sub.3.
[0086] Metrifonate has been used to treat Alzheimer's Disease (see
the studies of Cummings et al. "The efficacy of Metrifonate in
improving the behavioral disturbance of Alzheimer's disease
patients." Neurology 1998; 50:A251).
[0087] Echothiophate is also known as ecothiopate, echothiophate
iodide, phospholine iodide, (2-Mercaptoethyl)trimethylammonium
S-ester with O,O'-diethylphosphorothioate, BRN 1794025,
ecothiopatum, or phospholine. Echothiophate is referenced by CAS
Registry Number 6736-03-4.
[0088] In other embodiments, an AChE inhibitor is an aminoacridine
such as tacrine as a non-limiting example. Tacrine is also known as
tetrahydroaminoacridine or THA. Tacrine is referenced by CAS
Registry Number 321-64-2.
[0089] In additional embodiments, an AChE inhibitor is a carbamate
such as physostigmine, neostigmine, or rivastigmine as non-limiting
examples.
[0090] Physostigmine, also known as
1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-, methylcarbamate (ester)
or (3aS,8aR)-pyrrolo(2,3-b)indol-5-ol, is referenced by CAS number
57-47-6. It is a tertiary amine capable of crossing the blood-brain
barrier.
[0091] Neostigmine, or
m-hydroxyphenyl)trimethyl-dimethylcarbamate(ester) ammonium, is
referenced by CAS number 59-99-4.
[0092] Rivastigmine is also known as rivastigmine tartrate or
(S)--N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate
hydrogen-(2R,3R)-tartrate or SDZ ENA 713 or ENA 713. The reference
for rivastigmine is CAS Registry Number 123441-03-2.
[0093] In further embodiments, an AChE inhibitor is a carbamate
phenanthrine derivative such as galantamine or its hydrogen bromide
form as non-limiting examples.
[0094] Galantamine is also known as
(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro(3-
a,3,2-ef)(2)benzazepin-6-ol and is often used in its hydrogen
bromide form. Galantamine is referenced by CAS number 357-70-0.
[0095] An AChE inhibitor may also be a piperidine derivative, such
as donepezil as a non-limiting example. Donepezil is also known as
2,3-dihydro-5,6-dimethoxy-2-((1-(phenylmethyl)-4-piperidinyl)methyl)-1H-i-
nden-1-one, and is referenced by CAS number 120014-06-4.
[0096] Itopride may also be an AChE inhibitor for use in
embodiments disclosed herein. Itopride HCl is referenced by CAS
Registry Number 122898-67-3. In one embodiment, a total daily dose
range for itopride HCl is from about 25 mg to about 1000 mg, or
between about 100 mg to about 300 mg. In some embodiments, the AChE
inhibitor, or neurogenic agent, is the N-oxide derivative of
itopride, which is the primary human metabolite of itopride
HCl.
[0097] Another AChE inhibitor for use in the disclosed embodiments
is (-)-huperzine A, which is also referred to as HupA and
1-amino-13-ethylidene-11-methyl-6-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,-
10-trien-5-one. It is referenced by CAS number 102518-79-6.
[0098] A further embodiment of an AChE inhibitor is phenserine, the
structure and synthesis of which is described in U.S. Pat. No.
6,495,700, which is hereby incorporated by reference as if fully
set forth.
[0099] Methods for assessing the nature and/or degree of
neurogenesis in vivo and in vitro, for detecting changes in the
nature and/or degree of neurogenesis, for identifying neurogenesis
modulating agents, for isolating and culturing neural stem cells,
and for preparing neural stem cells for transplantation or other
purposes are disclosed, for example, in U.S. Provisional
Application No. 60/697,905, and U.S. Publication Nos. 2005/0009742
and 2005/0009847, 20050032702, 2005/0031538, 2005/0004046,
2004/0254152, 2004/0229291, and 2004/0185429, all of which are
herein incorporated by reference in their entirety.
[0100] Neurogenesis includes the differentiation of neural cells
along different potential lineages. In some embodiments, the
differentiation of neural stem or progenitor cells is along a
neuronal and/or glial cell lineage, optionally to the exclusion of
differentiation along an astrocyte lineage.
[0101] A muscarinic agent, such as an AChE inhibitor, as described
herein includes pharmaceutically acceptable salts, derivatives,
prodrugs, and metabolites of the inhibitor. Methods for preparing
and administering salts, derivatives, prodrugs, and metabolites of
various inhibitors are well known in the art.
[0102] Compounds described herein that contain a chiral center
include all possible stereoisomers of the compound, including
compositions comprising the racemic mixture of the two enantiomers,
as well as compositions comprising each enantiomer individually,
substantially free of the other enantiomer. Thus, for example,
contemplated herein is a composition comprising the S enantiomer of
a compound substantially free of the R enantiomer, or the R
enantiomer substantially free of the S enantiomer. If the named
compound comprises more than one chiral center, the scope of the
present disclosure also includes compositions comprising mixtures
of varying proportions between the diastereomers, as well as
compositions comprising one or more diastereomers substantially
free of one or more of the other diastereomers. By "substantially
free" it is meant that the composition comprises less than 25%,
15%, 10%, 8%, 5%, 3%, or less than 1% of the minor enantiomer or
diastereomer(s). Methods for synthesizing, isolating, preparing,
and administering various stereoisomers are known in the art.
[0103] Methods described herein can be used to treat any disease or
condition for which it is beneficial to promote or otherwise
stimulate or increase neurogenesis. One focus of the methods
described herein is to achieve a therapeutic result by increasing
neurogenesis. Thus, certain methods described herein can be used to
treat any disease or condition susceptible to treatment by
increasing neurogenesis.
[0104] In some embodiments, the disease or condition being treated
is associated with pain and/or addiction, but in contrast to known
methods, the disclosed treatments are substantially mediated by
increasing neurogenesis. For example, in some embodiments, methods
described herein involve increasing neurogenesis ex vivo, such that
a composition containing neural stem cells, neural progenitor
cells, and/or differentiated neural cells can subsequently be
administered to an individual to treat a disease or condition. In
some embodiments, methods described herein allow treatment of
diseases characterized by pain, addiction, and/or depression to be
treated by directly replenishing, replacing, and/or supplementing
neurons and/or glial cells. In further embodiments, methods
described herein enhance the growth and/or survival of existing
neural cells, and/or slow or reverse the loss of such cells in a
neurodegenerative condition.
[0105] Examples of diseases and conditions treatable by the methods
described herein include, but are not limited to, neurodegenerative
disorders and neural disease, such as dementias (e.g., senile
dementia, memory disturbances/memory loss, dementias caused by
neurodegenerative disorders (e.g., Alzheimer's, Parkinson's
disease, Parkinson's disorders, Huntington's disease (Huntington's
Chorea), Lou Gehrig's disease, multiple sclerosis, Pick's disease,
Parkinsonism dementia syndrome), progressive subcortical gliosis,
progressive supranuclear palsy, thalmic degeneration syndrome,
hereditary aphasia, amyotrophic lateral sclerosis, Shy-Drager
syndrome, and Lewy body disease; vascular conditions (e.g.,
infarcts, hemorrhage, cardiac disorders); mixed vascular and
Alzheimer's; bacterial meningitis; Creutzfeld-Jacob Disease; and
Cushing's disease.
[0106] The disclosed embodiments also provide for the treatment of
a nervous system disorder related to neural damage, cellular
degeneration, a psychiatric condition, cellular (neurological)
trauma and/or injury (e.g., subdural hematoma or traumatic brain
injury), toxic chemicals (e.g., heavy metals, alcohol, some
medications), CNS hypoxia, or other neurologically related
conditions. In practice, the disclosed compositions and methods may
be applied to a subject or patient afflicted with, or diagnosed
with, one or more central or peripheral nervous system disorders in
any combination. Diagnosis may be performed by a skilled person in
the applicable fields using known and routine methodologies which
identify and/or distinguish these nervous system disorders from
other conditions.
[0107] Non-limiting examples of nervous system disorders related to
cellular degeneration include neurodegenerative disorders, neural
stem cell disorders, neural progenitor cell disorders, degenerative
diseases of the retina, and ischemic disorders. In some
embodiments, an ischemic disorder comprises an insufficiency, or
lack, of oxygen or angiogenesis, and non-limiting example include
spinal ischemia, ischemic stroke, cerebral infarction,
multi-infarct dementia. While these conditions may be present
individually in a subject or patient, the disclosed methods also
provide for the treatment of a subject or patient afflicted with,
or diagnosed with, more than one of these conditions in any
combination.
[0108] Non-limiting embodiments of nervous system disorders related
to a psychiatric condition include neuropsychiatric disorders and
affective disorders. As used herein, an affective disorder refers
to a disorder of mood such as, but not limited to, depression,
post-traumatic stress disorder (PTSD), hypomania, panic attacks,
excessive elation, bipolar depression, bipolar disorder
(manic-depression), and seasonal mood (or affective) disorder.
Other non-limiting embodiments include schizophrenia and other
psychoses, lissencephaly syndrome, anxiety syndromes, anxiety
disorders, phobias, stress and related syndromes (e.g., panic
disorder, phobias, adjustment disorders, migraines), cognitive
function disorders, aggression, drug and alcohol abuse, drug
addiction, and drug-induced neurological damage, obsessive
compulsive behavior syndromes, borderline personality disorder,
non-senile dementia, post-pain depression, post-partum depression,
and cerebral palsy.
[0109] Examples of nervous system disorders related to cellular or
tissue trauma and/or injury include, but are not limited to,
neurological traumas and injuries, surgery related trauma and/or
injury, retinal injury and trauma, injury related to epilepsy, cord
injury, spinal cord injury, brain injury, brain surgery, trauma
related brain injury, trauma related to spinal cord injury, brain
injury related to cancer treatment, spinal cord injury related to
cancer treatment, brain injury related to infection, brain injury
related to inflammation, spinal cord injury related to infection,
spinal cord injury related to inflammation, brain injury related to
environmental toxin, and spinal cord injury related to
environmental toxin.
[0110] Non-limiting examples of nervous system disorders related to
other neurologically related conditions include learning disorders,
memory disorders, age-associated memory impairment (AAMI) or
age-related memory loss, autism, learning or attention deficit
disorders (ADD or attention deficit hyperactivity disorder, ADHD),
narcolepsy, sleep disorders and sleep deprivation (e.g., insomnia,
chronic fatigue syndrome), cognitive disorders, epilepsy, injury
related to epilepsy, and temporal lobe epilepsy.
[0111] Other non-limiting examples of diseases and conditions
treatable by the methods described herein include, but are not
limited to, hormonal changes (e.g., depression and other mood
disorders associated with puberty, pregnancy, or aging (e.g.,
menopause)); and lack of exercise (e.g., depression or other mental
disorders in elderly, paralyzed, or physically handicapped
patients); infections (e.g., HIV); genetic abnormalities (down
syndrome); metabolic abnormalities (e.g., vitamin B12 or folate
deficiency); hydrocephalus; memory loss separate from dementia,
including mild cognitive impairment (MCI), age-related cognitive
decline, and memory loss resulting from the use of general
anesthetics, chemotherapy, radiation treatment, post-surgical
trauma, or therapeutic intervention; and diseases of the of the
peripheral nervous system (PNS), including but not limited to, PNS
neuropathies (e.g., vascular neuropathies, diabetic neuropathies,
amyloid neuropathies, and the like), neuralgias, neoplasms,
myelin-related diseases, etc.
[0112] Additionally, the disclosed methods provide for the
application of a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent, to treat a subject or patient for a
condition due to the anti-neurogenic effects of an opiate or opioid
based analgesic. In some embodiments, the administration of an
opiate or opioid based analgesic, such as an opiate like morphine
or other opioid receptor agonist, to a subject or patient results
in a decrease in, or inhibition of, neurogenesis. The
administration of a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent, with an opiate or opioid based analgesic
would reduce the anti-neurogenic effect. One non-limiting example
is administration of a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent, with an opioid receptor agonist after
surgery (such as for the treating post-operative pain).
[0113] So the disclosed embodiments include a method of treating
post operative pain in a subject or patient by combining
administration of an opiate or opioid based analgesic with a
muscarinic agent, such as an AChE inhibitor, optionally in
combination with another muscarinic agent and/or another neurogenic
agent. The analgesic may have been administered before,
simultaneously with, or after a muscarinic agent, such as an AChE
inhibitor, alone or in combination with another neurogenic agent.
In some cases, the analgesic or opioid receptor agonist is morphine
or another opiate.
[0114] Other disclosed embodiments include a method to treat or
prevent decreases in, or inhibition of, neurogenesis in other cases
involving use of an opioid receptor agonist. The methods comprise
the administration of a muscarinic agent, such as an AChE
inhibitor, optionally in combination with another muscarinic agent
and/or another neurogenic agent, as described herein. Non-limiting
examples include cases involving an opioid receptor agonist, which
decreases or inhibits neurogenesis, and drug addiction, drug
rehabilitation, and/or prevention of relapse into addiction. In
some embodiments, the opioid receptor agonist is morphine, opium or
another opiate.
[0115] Compounds and compositions disclosed herein can also be used
to treat diseases of the peripheral nervous system (PNS), including
but not limited to, PNS neuropathies (e.g., vascular neuropathies,
diabetic neuropathies, amyloid neuropathies, and the like),
neuralgias, neoplasms, myelin-related diseases, etc.
[0116] Other conditions that can be beneficially treated by
increasing neurogenesis are known in the art (see e.g., U.S.
Publication Nos. 20020106731, 2005/0009742 and 2005/0009847,
20050032702, 2005/0031538, 2005/0004046, 2004/0254152,
2004/0229291, and 2004/0185429, herein incorporated by reference in
their entirety).
[0117] In some embodiments, a muscarinic agent, such as an AChE
inhibitor, optionally in combination with another muscarinic agent
and/or another neurogenic agent, used in the methods described
herein, is in the form of compositions that include at least one
pharmaceutically acceptable excipient. As used herein, the term
"pharmaceutically acceptable excipient" includes any excipient
known in the field as suitable for pharmaceutical application.
Suitable pharmaceutical excipients and formulations are known in
the art and are described, for example, in Remington's
Pharmaceutical Sciences (19th ed.) (Genarro, ed. (1995) Mack
Publishing Co., Easton, Pa.). Pharmaceutical carriers may be chosen
by a skilled person based upon the intended mode of administration
of a muscarinic agent. The pharmaceutically acceptable carrier may
include, for example, disintegrants, binders, lubricants, glidants,
emollients, humectants, thickeners, silicones, flavoring agents,
and water.
[0118] A muscarinic agent, such as an AChE inhibitor, may be
incorporated with excipients and administered in the form of
ingestible tablets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, or any other form known in the
pharmaceutical arts. The pharmaceutical compositions may also be
formulated in a sustained release form. Sustained release
compositions, enteric coatings, and the like are known in the art.
Alternatively, the compositions may be a quick release
formulation.
[0119] In some embodiments, methods of treatment disclosed herein
comprise the step of administering to a mammal a muscarinic agent,
such as an AChE inhibitor, optionally in combination with another
muscarinic agent and/or another neurogenic agent, for a time and at
a concentration sufficient to treat the condition targeted for
treatment. The disclosed methods can be applied to individuals
having, or who are likely to develop, disorders relating to neural
degeneration, neural damage and/or neural demyelination. In some
embodiments, a method comprises selecting a population or
sub-population of patients, or selecting an individual patient,
that is more amenable to treatment and/or less susceptible to side
effects than other patients having the same disease or condition.
For example, in some embodiments, a sub-population of patients is
identified as being more amenable to neurogenesis with a muscarinic
agent, such as an AChE inhibitor, optionally in combination with
another muscarinic agent and/or another neurogenic agent, by taking
a cell or tissue sample from prospective patients, isolating and
culturing neural cells from the sample, and determining the effect
of a muscarinic agent, such as an AChE inhibitor, optionally in
combination with another muscarinic agent and/or another neurogenic
agent, on the degree or nature of neurogenesis, thereby allowing
selection of patients for which a muscarinic agent, or combination
of neurogenic agents comprising it, has a substantial effect on
neurogenesis. Advantageously, the selection step(s) results in more
effective treatment for the disease or condition that known methods
using the same or similar compounds.
[0120] In other embodiments, the method of treatment comprises
identifying, generating, and/or propagating neural cells ex vivo in
contact with a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent, and transplanting the cells into a
subject. In another embodiment, the method of treatment comprises
the steps of contacting a neural stem cell of progenitor cell with
a muscarinic agent, such as an AChE inhibitor, optionally in
combination with another muscarinic agent and/or another neurogenic
agent, to stimulate neurogenesis, and transplanting the cells into
a patient in need of treatment. Also disclosed are methods for
preparing a population of neural stem cells suitable for
transplantation, comprising culturing a population of neural stem
cells (NSCs) in vitro, and contacting the cultured neural stem
cells with a muscarinic agent, such as an AChE inhibitor,
optionally in combination with another muscarinic agent and/or
another neurogenic agent, described herein. The disclosure further
includes methods of treating the diseases, disorders, and
conditions described herein by transplanting such cells into a
subject or patient.
[0121] Methods described herein may comprise administering to the
subject an effective amount of a muscarinic agent, such as an AChE
inhibitor, optionally in combination with another muscarinic agent
and/or another neurogenic agent, or pharmaceutical composition
comprising the muscarinic agent. In general, an effective amount of
compound(s) in the disclosed methods is an amount sufficient, when
used as described herein, to stimulate or increase neurogenesis in
the subject targeted for treatment when compared to the absence of
the compound. An effective amount of a composition may vary based
on a variety of factors, including but not limited to, the activity
of the active compound(s), the physiological characteristics of the
subject, the nature of the condition to be treated, and the route
and/or method of administration. The disclosed methods typically
involve the administration of a muscarinic agent, such as an
inhibitor of AChE activity, alone or in combination with another
neurogenic agent, in a dosage range of 0.001 ng/kg/day to 500
ng/kg/day or in a dosage range of 0.05 to 200 ng/kg/day.
Advantageously, methods described herein allow treatment of
indications with reductions in side effects, dosage levels, dosage
frequency, treatment duration, tolerability, and/or other
factors.
[0122] In some methods described herein, the application of a
muscarinic agent with selective activity towards one or more
muscarinic receptors may allow effective treatment with
substantially fewer and/or less severe side effects compared to
existing treatments. For example, muscarinic agents with
selectivity for m.sub.l receptors, which are primarily located in
the CNS, can reduce side effects associated with activity at
muscarinic receptors outside the intended target tissue/organ.
Similarly, the application of an AChE inhibitor in combination with
another muscarinic agent and/or another neurogenic agent may also
allow effective treatment with substantially fewer and/or less
severe side effects compared to other treatments. For example, each
neurogenic agent in a combination of agents may be present in an
amount that results in fewer and/or less severe side effects than
that which occurs with a larger amount. Thus the combined effect of
the neurogenic agents will provide a desired neurogenic activity
while exhibiting fewer and/or less severe side effects overall.
[0123] As non-limiting examples, fluoxetine has been reported to
result in problems such as sexual dysfunction and (rarely)
agitation and increased suicidal thoughts after acute
administration at high doses. Sabcomeline has been reported to have
dose limiting toxicities in the clinic from excessive sweating,
nausea, vomiting and diarrhea. As shown in FIG. 13, however, the
combination of these two compounds at doses that are individually
sub-therapeutic in reference to clinical reports (and in promoting
neurogenesis and anti-depressant activity in vivo by assays
described herein) results in efficacy in a model of depression and
is observed to promote neurogenesis. The sub-therapeutic doses are
believed to be below those reported as associated with severe or
significant side effects.
[0124] Established methods of treating various conditions of the
CNS and PNS with compounds having activity against muscarinic
receptors have been known to cause side effects including, but not
limited to, sweating, diarrhea, flushing, hypotension, bradycardia,
bronchoconstriction, urinary bladder contraction, nausea, vomiting,
parkinsonism, and increased mortality risk. In some embodiments,
methods described herein allow treatment of certain conditions for
which treatment with the same or similar compounds is ineffective
using known methods due, for example, to dose-limiting side
effects. As non-limiting examples, methods comprising the use of
reduced amounts of a muscarinic agent, such as an AChE inhibitor,
in combination with another muscarinic agent and/or another
neurogenic agent, as described herein treats certain conditions
with minimization of these side effects.
[0125] Depending on the desired clinical result, the disclosed
neurogenic agents or pharmaceutical compositions are administered
by any means suitable for achieving a desired effect. Various
delivery methods are known in the art and can be used to deliver an
agent to a subject or to NSCs or progenitor cells within a tissue
of interest. The delivery method will depend on factors such as the
tissue of interest, the nature of the compound (e.g., its stability
and ability to cross the blood-brain barrier), and the duration of
the experiment, among other factors. For example, an osmotic
minipump can be implanted into a neurogenic region, such as the
lateral ventricle. Alternatively, compounds can be administered by
direct injection into the cerebrospinal fluid of the brain or
spinal column, or into the eye. Compounds can also be administered
into the periphery (such as by intravenous or subcutaneous
injection, or oral delivery), and subsequently cross the
blood-brain barrier.
[0126] In various embodiments, the disclosed agents or
pharmaceutical compositions are administered in a manner that
allows them to contact the subventricular zone (SVZ) of the lateral
ventricles and/or the dentate gyrus of the hippocampus. Examples of
routes of administration include parenteral, e.g., intravenous,
intradermal, subcutaneous, oral (e.g., inhalation), transdermal
(topical), transmucosal, and rectal administration. Intranasal
administration generally includes, but is not limited to,
inhalation of aerosol suspensions for delivery of compositions to
the nasal mucosa, trachea and bronchioli.
[0127] In some embodiments, the compound combinations are
administered so as to either pass through or by-pass the
blood-brain barrier. Methods for allowing factors to pass through
the blood-brain barrier are known in the art, and include
minimizing the size of the factor, providing hydrophobic factors
which facilitate passage, and conjugating a muscarinic agent, such
as an inhibitor of AChE activity, to a carrier molecule that has
substantial permeability across the blood brain barrier. In some
instances, the combination of compounds can be administered by a
surgical procedure implanting a catheter coupled to a pump device.
The pump device can also be implanted or be extracorporally
positioned. Administration of the muscarinic agent can be in
intermittent pulses or as a continuous infusion. Devices for
injection to discrete areas of the brain are known in the art. In
certain embodiments, the muscarinic agent is administered locally
to the ventricle of the brain, substantia nigra, striatum, locus
ceruleous, nucleus basalis Meynert, pedunculopontine nucleus,
cerebral cortex, and/or spinal cord by, e.g., injection. Methods,
compositions, and devices for delivering therapeutics, including
therapeutics for the treatment of diseases and conditions of the
CNS and PNS, are known in the art.
[0128] In some embodiments, the delivery or targeting of a
muscarinic agent, such as an inhibitor of AChE activity, to a
neurogenic region, such as the dentate gyrus or the subventricular
zone, enhances efficacy and reduces side effects compared to known
methods involving administration with the same or similar
compounds.
[0129] In embodiments to treat subjects and patients, the methods
include identifying a patient suffering from one or more disease,
disorders, or conditions, or a symptom thereof, and administering
to the subject or patient at least one muscarinic agent, such as an
inhibitor of AChE activity, as described herein. The identification
of a subject or patient as having one or more disease, disorder or
condition, or a symptom thereof, may be made by a skilled
practitioner using any appropriate means known in the field.
[0130] In further embodiments, the methods may be used to treat a
cell, tissue, or subject which is exhibiting decreased neurogenesis
or increased neurodegeneration. In some cases, the cell, tissue, or
subject is, or has been, subjected to, or contacted with, an agent
that decreases or inhibits neurogenesis. One non-limiting example
is a human subject that has been administered morphine or other
agent which decreases or inhibits neurogenesis. Non-limiting
examples of other agents include opiates and opioid receptor
agonists, such as mu receptor subtype agonists, that inhibit or
decrease neurogenesis.
[0131] Thus in additional embodiments, the methods may be used to
treat subjects having, or diagnosed with, depression or other
withdrawal symptoms from morphine or other agents which decrease or
inhibit neurogenesis. This is distinct from the treatment of
subjects having, or diagnosed with, depression independent of an
opiate, such as that of a psychiatric nature, as disclosed herein.
In further embodiments, the methods may be used to treat a subject
with one or more chemical addiction or dependency, such as with
morphine or other opiates, where the addiction or dependency is
ameliorated or alleviated by an increase in neurogenesis.
[0132] In some embodiments, such as those for treating depression
and other neurological diseases and conditions, the methods may
optionally further comprise use of one or more agents reported as
anti-depressant agents. Thus a method may comprise treatment with a
muscarinic agent, such as an inhibitor of AChE activity, and one or
more reported anti-depressant agents as known to the skilled
person. Non-limiting examples of such agents include an S SRI
(selective serotonine reuptake inhibitor), such as fluoxetine
(Prozac.RTM.), citalopram (Celexa), escitalopram (Lexapro),
fluvoxamine or fluvoxamine maleate (CAS RN: 61718-82-9) and
Luvox.RTM., paroxetine (Paxil.RTM.), or sertraline (Zoloft.RTM.);
the compound nefazodone (Serozone.RTM.); a selective norepinephrine
reuptake inhibitor (SNRI) such as reboxetine (Edronax.RTM.) or
atomoxetine (Strattera.RTM.); a selective serotonin &
norepinephrine reuptake inhibitor (SSNRI) such as venlafaxine
(Effexor), and its reported metabolite desvenlafaxine, or
duloxetine (Cymbalta); a serotonin, noradrenaline, and dopamine
"triple uptake inhibitor", such as
[0133] DOV 102,677 (see Popik et al. "Pharmacological Profile of
the "Triple" Monoamine Neurotransmitter Uptake Inhibitor, DOV
102,677." Cell Mol Neurobiol. 2006 Apr. 25; Epub ahead of
print),
[0134] DOV 216,303 (see Beer et al. "DOV 216,303, a "triple"
reuptake inhibitor: safety, tolerability, and pharmacokinetic
profile." J Clin Pharmacol. 2004 44(12):1360-7),
[0135] DOV 21,947
((+)-1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane
hydrochloride), see Skolnick et al. "Antidepressant-like actions of
DOV 21,947: a "triple" reuptake inhibitor." Eur J Pharmacol. 2003
461(2-3):99-104),
[0136] NS-2330 or tesofensine (CAS RN 402856-42-2), or NS 2359 (CAS
RN 843660-54-8);
[0137] and agents like dehydroepiandrosterone (DHEA), and DHEA
sulfate (DHEAS), CP-122,721 (CAS RN 145742-28-5).
[0138] Additional non-limiting examples of such agents include a
tricyclic compound such as amitriptyline, desipramine, doxepin,
imipramine, or nortriptyline; a psychostimulant such as
dextroamphetamine and methylphenidate; an MAO inhibitor such as
selegiline (Emsam.RTM.); an ampakine such as CX516 (or Ampalex, CAS
RN: 154235-83-3), CX546 (or
1-(1,4-benzodioxan-6-ylcarbonyl)piperidine), and CX614 (CAS RN
191744-13-5) from Cortex Pharmaceuticals; a V1b antagonist such as
SSR149415
((2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-met-
hoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyr-
rolidine carboxamide),
[0139] [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic
acid), 2-O-ethyltyrosine, 4-valine]arginine vasopressin
(d(CH2)5[Tyr(Et2)]VAVP (WK 1-1),
[0140]
9-desglycine[1-(beta-mercapto-beta,beta-cyclopentamethylenepropioni-
c acid), 2-O-ethyltyrosine, 4-valine]arginine vasopressin
desGly9d(CH2)5 [Tyr(Et2)]-VAVP (WK 3-6), or
[0141]
9-desglycine[1-(beta-mercapto-beta,beta-cyclopentamethylenepropioni-
c acid),2-D-(O-ethyl)tyrosine, 4-valine]arginine vasopressin des
Gly9d(CH2)5[D-Tyr(Et2)]VAVP (AO 3-21); a corticotropin-releasing
factor (CRF) R antagonist such as CP-154,526 (structure disclosed
in Schulz et al. "CP-154,526: a potent and selective nonpeptide
antagonist of corticotropin releasing factor receptors." Proc Natl
Acad Sci USA. 1996 93(19):10477-82), NBI 30775 (also known as
R121919 or
2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-'7-dipropylaminopyrazolo-
[1,5-a]pyrimidine), astressin (CAS RN 170809-51-5), or a
photoactivatable analog thereof as described in Bonk et al. "Novel
high-affinity photoactivatable antagonists of
corticotropin-releasing factor (CRF)" Eur. J. Biochem.
267:3017-3024 (2000), or AAG561 (from Novartis); a melanin
concentrating hormone (MCH) antagonist such as
3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide
or
(R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide
(see Kim et al. "Identification of substituted 4-aminopiperidines
and 3-aminopyrrolidines as potent MCH-R1 antagonists for the
treatment of obesity." Bioorg Med Chem Lett. 2006 Jul. 29; [Epub
ahead of print] for both), or any MCH antagonist disclosed in U.S.
Pat. No. 7,045,636 or published U.S. Patent Application
US2005/0171098.
[0142] Further non-limiting examples of such agents include
agomelatine (CAS RN 138112-76-2), mirtazapine (CAS RN 61337-67-5,
also known as Remeron, or CAS RN 85650-52-8), pindolol (CAS RN
13523-86-9), antalarmin (CAS RN 157284-96-3), mifepristone (CAS RN
84371-65-3), nemifitide (CAS RN 173240-15-8) or nemifitide
ditriflutate (CAS RN 204992-09-6), YKP-10A or R228060 (CAS RN
561069-23-6), trazodone (CAS RN 19794-93-5), bupropion (CAS RN
34841-39-9 or 34911-55-2) or bupropion hydrochloride (or
Wellbutrin, CAS RN 31677-93-7) and its reported metabolite
radafaxine (CAS RN 192374-14-4), NS2359 (CAS RN 843660-54-8), Org
34517 (CAS RN 189035-07-2), Org 34850 (CAS RN 162607-84-3),
vilazodone (CAS RN 163521-12-8), CP-122,721 (CAS RN 145742-28-5),
gepirone (CAS RN 83928-76-1), SR58611 (see Mizuno et al. "The
stimulation of beta(3)-adrenoceptor causes phosphorylation of
extracellular signal-regulated kinases 1 and 2 through a G(s)--but
not G(i)-dependent pathway in 3T3-L1 adipocytes." Eur J Pharmacol.
2000 404(1-2):63-8), saredutant or SR 48968 (CAS RN 142001-63-6),
PRX-00023
(N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}ace-
tamide, see Becker et al. "An integrated in silico 3D model-driven
discovery of a novel, potent, and selective amidosulfonamide 5-HT1A
agonist (PRX-00023) for the treatment of anxiety and depression." J
Med Chem. 2006 49(11):3116-35), Vestipitant (or GW597599, CAS RN
334476-46-9), OPC-14523 or VPI-013 (see Bermack et al. "Effects of
the potential antidepressant OPC-14523
[1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-q-
uinolinone monomethanesulfonate] a combined sigma and 5-HT1A
ligand: modulation of neuronal activity in the dorsal raphe
nucleus." J Pharmacol Exp Ther. 2004 310(2):578-83), Casopitant or
GW679769 (CAS RN 852393-14-7), Elzasonan or CP-448,187 (CAS RN
361343-19-3), GW823296 (see published U.S. Patent Application
US2005/0119248), Delucemine or NPS 1506 (CAS RN 186495-49-8), or
Ocinaplon (CAS RN 96604-21-6).
[0143] Yet additional non-limiting examples of such agents include
CX717 from Cortex Pharmaceuticals, TGBA01AD (a serotonin reuptake
inhibitor, 5-HT2 agonist, 5-HT1A agonist, and 5-HT1D agonist) from
Fabre-Kramer Pharmaceuticals, Inc., ORG 4420 (an NaSSA
(noradrenergic/specific serotonergic antidepressant) from Organon,
CP-316,311 (a CRF1 antagonist) from Pfizer, BMS-562086 (a CRF1
antagonist) from Bristol-Myers Squibb, GW876008 (a CRF1 antagonist)
from Neurocrine/GlaxoSmithKline, ONO-2333Ms (a CRF1 antagonist)
from Ono Pharmaceutical Co., Ltd., JNJ-19567470 or TS-041 (a CRF1
antagonist) from Janssen (Johnson & Johnson) and Taisho, SSR
125543 or SSR 126374 (a CRF1 antagonist) from Sanofi-Aventis, Lu
AA21004 and Lu AA24530 (both from H. Lundbeck A/S), SEP-225289 from
Sepracor Inc., ND7001 (a PDE2 inhibitor) from Neuro3d, SSR 411298
or SSR 101010 (a fatty acid amide hydrolase, or FAAH, inhibitor)
from Sanofi-Aventis, 163090 (a mixed serotonin receptor inhibitor)
from GlaxoSmithKline, SSR 241586 (an NK2 and NK3 receptor
antagonist) from Sanofi-Aventis, SAR 102279 (an NK2 receptor
antagonist) from Sanofi-Aventis, YKP581 from SK Pharmaceuticals
(Johnson & Johnson), R1576 (a GPCR modulator) from Roche, or
ND1251 (a PDE4 inhibitor) from Neuro3d.
[0144] Specific embodiments of the disclosure include combinations
of each one of the above reported anti-depressants with sabcomeline
for use in the disclosed methods. The efficacy of a combination of
a muscarinic agent, such as an inhibitor of AChE activity, and an
antidepressant is shown in FIGS. 13A and 13B.
[0145] In other disclosed embodiments, a reported anti-psychotic
agent may be used in combination with a muscarinic agent, such as
an inhibitor of AChE activity. Non-limiting examples of a reported
anti-psychotic agent as a member of a combination include
olanzapine, quetiapine (Seroquel), clozapine (CAS RN 5786-21-0) or
its metabolite ACP-104 (N-desmethylclozapine or norclozapine, CAS
RN 6104-71-8), reserpine, aripiprazole, risperidone, ziprasidone,
paliperidone (CAS RN 144598-75-4), mifepristone (CAS RN
84371-65-3), bifeprunox or DU-127090 (CAS RN 350992-10-8),
asenapine or ORG 5222 (CAS RN 65576-45-6), iloperidone (CAS RN
133454-47-4), ocaperidone (CAS RN 129029-23-8), SLV 308 (CAS RN
269718-83-4), licarbazepine or GP 47779 (CAS RN 29331-92-8), Org
34517 (CAS RN 189035-07-2), ORG 34850 (CAS RN 162607-84-3), Org
24448 (CAS RN 211735-76-1), lurasidone (CAS RN 367514-87-2),
blonanserin or lonasen (CAS RN 132810-10-7), Talnetant or SB-223412
(CAS RN 174636-32-9), secretin (CAS RN 1393-25-5) or human secretin
(CAS RN 108153-74-8) which are endogenous pancreatic hormones, ABT
089 (CAS RN 161417-03-4), SSR 504734 (see compound 13 in Hashimoto
"Glycine Transporter Inhibitors as Therapeutic Agents for
Schizophrenia." Recent Patents on CNS Drug Discovery, 2006
1:43-53), MEM 3454 (see Mazurov et al. "Selective alpha7 nicotinic
acetylcholine receptor ligands." Curr Med Chem. 2006
13(13):1567-84), a phosphodiesterase 10A (PDE10A) inhibitor such as
papaverine (CAS RN 58-74-2) or papaverine hydrochloride (CAS RN
61-25-6), paliperidone (CAS RN 144598-75-4), trifluoperazine (CAS
RN 117-89-5), or trifluoperazine hydrochloride (CAS RN
440-17-5).
[0146] Additional non-limiting examples of such agents include
trifluoperazine, fluphenazine, chlorpromazine, perphenazine,
thioridazine, haloperidol, loxapine, mesoridazine, molindone,
pimoxide, or thiothixene, SSR 146977 (see Emonds-Alt et al.
"Biochemical and pharmacological activities of SSR 146977, a new
potent nonpeptide tachykinin NK3 receptor antagonist." Can J
Physiol Pharmacol. 2002 80(5):482-8), SSR181507
((3-exo)-8-benzoyl-N-[[(2
s)7-chloro-2,3-dihydro-1,4-benzodioxin-l-yl]methyl]-8-azabicyclo[3.2.1]oc-
tane-3-methanamine monohydrochloride), or SLV313
(1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-yl-
methyl]-piperazine).
[0147] Further non-limiting examples of such agents include
Lu-35-138 (a D4/5-HT antagonist) from Lundbeck, AVE 1625 (a CB1
antagonist) from Sanofi-Aventis, SLV 310,313 (a 5-HT2A antagonist)
from Solvay, SSR 181507 (a D2/5-HT2 antagonist) from
Sanofi-Aventis, GW07034 (a 5-HT6 antagonist) or GW773812 (a D2,
5-HT antagonist) from GlaxoSmithKline, YKP 1538 from SK
Pharmaceuticals, SSR 125047 (a sigma receptor antagonist) from
Sanofi-Aventis, MEM1003 (a L-type calcium channel modulator) from
Memory Pharmaceuticals, JNJ-17305600 (a GLYT1 inhibitor) from
Johnson & Johnson, XY 2401 (a glycine site specific NMDA
modulator) from Xytis, PNU 170413 from Pfizer, RGH-188 (a D2, D3
antagonist) from Forrest, SSR 180711 (an alpha7 nicotinic
acetylcholine receptor partial agonist) or SSR 103800 (a GLYT1
(Type 1 glycine transporter) inhibitor) or SSR 241586 (a NK3
antagonist) from Sanofi-Aventis.
[0148] In light of the positive recitation (above and below) of
combinations with alternative agents to treat conditions disclosed
herein, the disclosure includes embodiments with the explicit
exclusion of one or more of the alternative agents. As would be
recognized by the skilled person, a description of the whole of a
plurality of alternative agents necessarily includes and describes
subsets of the possible alternatives, or the part remaining with
the exclusion of one or more of the alternatives.
[0149] The combination therapy may be of one of the above with a
muscarinic agent, such as an inhibitor of AChE activity, as
described herein to improve the condition of the subject or
patient. Non-limiting examples of combination therapy include the
use of lower dosages of the above which reduce side effects of the
anti-depressant agent when used alone. For example, an
anti-depressant agent like fluoxetine or paroxetine or sertraline
may be administered at a reduced or limited dose, optionally also
reduced in frequency of administration, in combination with a
muscarinic agent, such as an inhibitor of AChE activity, alone or
in combination with another muscarinic agent and/or another
neurogenic agent. The reduced dose or frequency mediates a
sufficient anti-depressant effect so that the side effects of the
anti-depressant agent alone are reduced or eliminated. See FIG.
13.
[0150] In additional embodiments, such as, but not limited to,
treating weight gain, metabolic syndrome, or obesity, and/or to
induce weight loss, a muscarinic agent, such as an inhibitor of
AChE activity, alone or in combination with another muscarinic
agent and/or neurogenic agent, may be used in combination.
Non-limiting examples of another agent include those reported for
treating weight gain or metabolic syndrome and/or inducing weight
loss such as various diet pills that are commercially or clinically
available. In some embodiments, the reported agent for treating
weight gain, metabolic syndrome, obesity, or for inducing weight
loss is orlistat (CAS RN 96829-58-2), sibutramine (CAS RN
106650-56-0) or sibutramine hydrochloride (CAS RN 84485-00-7),
phetermine (CAS RN 122-09-8) or phetermine hydrochloride (CAS RN
1197-21-3), diethylpropion or amfepramone (CAS RN 90-84-6) or
diethylpropion hydrochloride, benzphetamine (CAS RN 156-08-1) or
benzphetamine hydrochloride, phendimetrazine (CAS RN 634-03-7 or
21784-30-5) or phendimetrazine hydrochloride (CAS RN 17140-98-6) or
phendimetrazine tartrate, rimonabant (CAS RN 168273-06-1),
bupropion hydrochloride (CAS RN: 31677-93-7), topiramate (CAS RN
97240-79-4), zonisamide (CAS RN 68291-97-4), or APD-356 (CAS RN
846589-98-8).
[0151] In other non-limiting embodiments, the agent may be
fenfluramine or Pondimin (CAS RN 458-24-2), dexfenfluramine or
Redux (CAS RN 3239-44-9), or levofenfluramine (CAS RN 37577-24-5);
or a combination thereof or a combination with phentermine.
Non-limiting examples include a combination of fenfluramine and
phentermine (or "fen-phen") and of dexfenfluramine and phentermine
(or "dexfen-phen").
[0152] The combination therapy may be of one of the above with a
muscarinic agent, such as an inhibitor of AChE activity, as
described herein to improve the condition of the subject or
patient. Non-limiting examples of combination therapy include the
use of lower dosages of the above additional agents, or
combinations thereof, which reduce side effects of the agent or
combination when used alone. For example, a combination of
fenfluramine and phentermine, or phentermine and dexfenfluramine,
may be administered at a reduced or limited dose, optionally also
reduced in frequency of administration, in combination with a
muscarinic agent, such as an inhibitor of AChE activity, alone or
in combination with another muscarinic agent and/or another
neurogenic agent. The reduced dose or frequency may be that which
reduces or eliminates the side effects of the combination.
[0153] As indicated herein, the disclosure includes combination
therapy, where one or more muscarinic agent, such as inhibitors of
AChE activity, and one or more other compounds are used together to
produce neurogenesis. When administered as a combination, the
therapeutic compounds can be formulated as separate compositions
that are administered at the same time or sequentially at different
times, or the therapeutic compounds can be given as a single
composition. The methods of the disclosure are not limited in the
sequence of administration.
[0154] Instead, the disclosure includes methods wherein treatment
with a muscarinic agent, such as an inhibitor of AChE activity, and
another muscarinic agent and/or neurogenic agent occurs over a
period of more than about 48 hours, more than about 72 hours, more
than about 96 hours, more than about 120 hours, more than about 144
hours, more than about 7 days, more than about 9 days, more than
about 11 days, more than about 14 days, more than about 21 days,
more than about 28 days, more than about 35 days, more than about
42 days, more than about 49 days, more than about 56 days, more
than about 63 days, more than about 70 days, more than about 77
days, more than about 12 weeks, more than about 16 weeks, more than
about 20 weeks, or more than about 24 weeks or more. In some
embodiments, treatment by administering a muscarinic agent, such as
an inhibitor of AChE activity, occurs at least about 12 hours, such
as at least about 24, or at least about 36 hours, before
administration of another neurogenic agent. Following
administration of a muscarinic agent, such as an inhibitor of AChE
activity, further administrations may be of only the other
neurogenic agent in some embodiments of the disclosure. In other
embodiments, further administrations may be of only the muscarinic
agent.
[0155] In other embodiments, the neurogenic agent combined with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported opioid or non-opioid (acts independently of an opioid
receptor) agent. In some embodiments, the neurogenic agent is one
reported as antagonizing one or more opioid receptors or as an
inverse agonist of at least one opioid receptor. A opioid receptor
antagonist or inverse agonist may be specific or selective (or
alternatively non-specific or non-selective) for opioid receptor
subtypes. So an antagonist may be non-specific or non-selective
such that it antagonizes more than one of the three known opioid
receptor subtypes, identified as OP.sub.1, OP.sub.2, and OP.sub.3
(also know as delta, or .delta., kappa, or .kappa., and mu, or
.mu., respectively). Thus an opioid that antagonizes any two, or
all three, of these subtypes, or an inverse agonist that is
specific or selective for any two or all three of these subtypes,
may be used as the neurogenic agent in the practice. Alternatively,
an antagonist or inverse agonist may be specific or selective for
one of the three subtypes, such as the kappa subtype as a
non-limiting example.
[0156] Non-limiting examples of reported opioid antagonists include
naltrindol, naloxone, naloxene, naltrexone, JDTic (Registry Number
785835-79-2; also known as 3-isoquinolinecarboxamide,
1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4--
dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-dihydrochloride,
(3R)-(9CI)), nor-binaltorphimine, and buprenorphine. In some
embodiments, a reported selective kappa opioid receptor antagonist
compound, as described in US 20020132828, U.S. Pat. No. 6,559,159,
and/or WO 2002/053533, may be used. All three of these documents
are herein incorporated by reference in their entireties as if
fully set forth. Further non-limiting examples of such reported
antagonists is a compound disclosed in U.S. Pat. No. 6,900,228
(herein incorporated by reference in its entirety), arodyn
(Ac[Phe(1,2,3),Arg(4),d-Ala(8)]Dyn A-(1-11)NH(2), as described in
Bennett, et al. (2002) J. Med. Chem. 45:5617-5619), and an active
analog of arodyn as described in Bennett e al. (2005) J Pept Res.
65(3):322-32, alvimopan.
[0157] In some embodiments, the neurogenic agent used in the
methods described herein has "selective" activity (such as in the
case of an antagonist or inverse agonist) under certain conditions
against one or more opioid receptor subtypes with respect to the
degree and/or nature of activity against one or more other opioid
receptor subtypes. For example, in some embodiments, the neurogenic
agent has an antagonist effect against one or more subtypes, and a
much weaker effect or substantially no effect against other
subtypes. As another example, an additional neurogenic agent used
in the methods described herein may act as an agonist at one or
more opioid receptor subtypes and as antagonist at one or more
other opioid receptor subtypes.
[0158] In some embodiments, a neurogenic agent has activity against
kappa opioid receptors, while having substantially lesser activity
against one or both of the delta and mu receptor subtypes. In other
embodiments, a neurogenic agent has activity against two opioid
receptor subtypes, such as the kappa and delta subtypes. As
non-limiting examples, the agents naloxone and naltrexone have
nonselective antagonist activities against more than one opioid
receptor subtypes. In certain embodiments, selective activity of
one or more opioid antagonists results in enhanced efficacy, fewer
side effects, lower effective dosages, less frequent dosing, or
other desirable attributes.
[0159] An opioid receptor antagonist is an agent able to inhibit
one or more characteristic responses of an opioid receptor or
receptor subtype. As a non-limiting example, an antagonist may
competitively or non-competitively bind to an opioid receptor, an
agonist or partial agonist (or other ligand) of a receptor, and/or
a downstream signaling molecule to inhibit a receptor's
function.
[0160] An inverse agonist able to block or inhibit a constitutive
activity of an opioid receptor may also be used. An inverse agonist
may competitively or non-competitively bind to an opioid receptor
and/or a downstream signaling molecule to inhibit a receptor's
function. Non-limiting examples of inverse agonists for use in the
disclosed methods include ICI-174864
(N,N-diallyl-Tyr-Aib-Aib-Phe-Leu), RTI-5989-1, RTI-5989-23, and
RTI-5989-25 (see Zaki et al. J Pharmacol. Exp. Therap. 298(3):
1015-1020, 2001).
[0161] In further non-limiting embodiments, the neurogenic agent in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be acetylcholine.
[0162] In yet further non-limiting embodiments, the neurogenic
agent in combination with a muscarinic agent, such as an inhibitor
of AChE activity, may be a reported modulator of an androgen
receptor. Non-limiting examples include the androgen receptor
agonists ehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS).
[0163] Alternatively, the neurogenic agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be an
enzymatic inhibitor, such as a reported inhibitor of HMG CoA
reductase. Non-limiting examples of such inhibitors include
atorvastatin (CAS RN 134523-00-5), cerivastatin (CAS RN
145599-86-6), crilvastatin (CAS RN 120551-59-9), fluvastatin (CAS
RN 93957-54-1) and fluvastatin sodium (CAS RN 93957-55-2),
simvastatin (CAS RN 79902-63-9), lovastatin (CAS RN 75330-75-5),
pravastatin (CAS RN 81093-37-0) or pravastatin sodium, rosuvastatin
(CAS RN 287714-41-4), and simvastatin (CAS RN 79902-63-9).
Formulations containing one or more of such inhibitors may also be
used in a combination. Non-limiting examples include formulations
comprising lovastatin such as Advicor (an extended-release, niacin
containing formulation) or Altocor (an extended release
formulation); and formulations comprising simvastatin such as
Vytorin (combination of simvastatin and ezetimibe).
[0164] In other non-limiting embodiments, the neurogenic agent in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be a reported Rho kinase inhibitor. Non-limiting
examples of such an inhibitor include fasudil (CAS RN 103745-39-7);
fasudil hydrochloride (CAS RN 105628-07-7); the metabolite of
fasudil, which is hydroxyfasudil (see Shimokawa et al.
"Rho-kinase-mediated pathway induces enhanced myosin light chain
phosphorylations in a swine model of coronary artery spasm."
Cardiovasc Res. 1999 43:1029-1039), Y 27632 (CAS RN 138381-45-0); a
fasudil analog thereof such as
(S)-Hexahydro-1-(4-ethenylisoquinoline-5-sulfonyl)-2-methyl-1H-1,4-diazep-
ine,
(S)-hexahydro-4-glycyl-2-methyl-1-(4-methylisoquinoline-5-sulfonyl)-1-
H-1,4-diazepine, or
(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine
(also known as H-1152P; see Sasaki et al. "The novel and specific
Rho-kinase inhibitor
(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine
as a probing molecule for Rho-kinase-involved pathway." Pharmacol
Ther. 2002 93(2-3):225-32); or a substituted
isoquinolinesulfonamide compound as disclosed in U.S. Pat. No.
6,906,061.
[0165] Furthermore, the neurogenic agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported GSK-3 inhibitor or modulator. In some non-limiting
embodiments, the reported GSK3-beta modulator is a paullone, such
as alsterpaullone, kenpaullone
(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one),
gwennpaullone (see Knockaert et al. "Intracellular Targets of
Paullones. Identification following affinity purification on
immobilized inhibitor." J Biol Chem. 2002 277(28):25493-501),
azakenpaullone (see Kunick et al. "1-Azakenpaullone is a selective
inhibitor of glycogen synthase kinase-3 beta." Bioorg Med Chem
Lett. 2004 14(2):413-6), or the compounds described in U.S,
Publication No. 20030181439; International Publication No. WO
01/60374; Leost et al., Eur. J. Biochem. 267:5983-5994 (2000);
Kunick et al., J Med Chem.; 47(1): 22-36 (2004); or Shultz et al.,
J. Med. Chem. 42:2909-2919 (1999); an anticonvulsant, such as
lithium or a derivative thereof (e.g., a compound described in U.S.
Pat. Nos. 1,873,732; 3,814,812; and 4,301,176); valproic acid or a
derivative thereof (e.g., valproate, or a compound described in
Werstuck et al., Bioorg Med Chem Lett., 14(22): 5465-7 (2004));
lamotrigine; SL 76002 (Progabide), Gabapentin; tiagabine; or
vigabatrin; a maleimide or a related compound, such as Ro 31-8220,
SB-216763, SB-410111, SB-495052, or SB-415286, or a compound
described, e.g., in U.S. Pat. No. 6,719,520; U.S. Publication No.
20040010031; International Publication Nos. WO-2004072062;
WO-03082859; WO-03104222; WO-03103663, WO-03095452, WO-2005000836;
WO 0021927; WO-03076398; WO-00021927; WO-00038675; or WO-03076442;
or Coghlan et al., Chemistry & Biology 7: 793 (2000); a
pyridine or pyrimidine derivative, or a related compound (such as
5-iodotubercidin, GI 179186X, GW 784752X and GW 784775X, and
compounds described, e.g., in U.S. Pat. Nos. 6,489,344; 6,417,185;
and 6,153,618; U.S. Publication Nos. 20050171094; and 20030130289;
European Patent Nos. EP-01454908, EP-01454910, EP-01295884,
EP-01295885; and EP-01460076; EP-01454900; International
Publication Nos. WO 01/70683; WO 01/70729; WO 01/70728; WO
01/70727; WO 01/70726; WO 01/70725; WO-00218385; WO-00218386;
WO-03072579; WO-03072580; WO-03027115; WO-03027116; WO-2004078760;
WO-2005037800, WO-2004026881, WO-03076437, WO-03029223;
WO-2004098607; WO-2005026155; WO-2005026159; WO-2005025567;
WO-03070730 ; WO-03070729; WO-2005019218; WO-2005019219;
WO-2004013140; WO-2004080977; WO-2004026229, WO-2004022561;
WO-03080616; WO-03080609; WO-03051847; WO-2004009602;
WO-2004009596; WO-2004009597; WO-03045949; WO-03068773;
WO-03080617; WO 99/65897; WO 00/18758; WO0307073; WO-00220495;
WO-2004043953, WO-2004056368, WO-2005012298, WO-2005012262,
WO-2005042525, WO-2005005438, WO-2004009562, WO-03037877;
WO-03037869; WO-03037891; WO-05012307; WO-05012304 and WO 98/16528;
and in Massillon et al., Biochem J 299:123-8 (1994)); a pyrazine
derivative, such as Aloisine A
(7-n-Butyl-6-(4-hydroxyphenyl)[5H]pyrrolo[2,3-b]pyrazine) or a
compound described in International Publication Nos. WO-00144206;
WO0144246; or WO-2005035532; a thiadiazole or thiazole, such as
TDZD-8 (Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione); OTDZT
(4-Dibenzyl-5-oxothiadiazolidine-3-thione); or a related compound
described, e.g., in U.S. Pat. Nos. 6,645,990 or 6,762,179; U.S.
Publication No. 20010039275; International Publication Nos. WO
01/56567, WO-03011843, WO-03004478, or WO-03089419; or Mettey, Y.,
et al., J. Med. Chem. 46, 222 (2003); TWS119 or a related compound,
such as a compound described in Ding et al., Proc Natl Acad Sci
USA., 100(13): 7632-7 (2003); an indole derivative, such as a
compound described in International Publication Nos. WO-03053330,
WO-03053444, WO-03055877, WO-03055492, WO-03082853, or
WO-2005027823; a pyrazine or pyrazole derivative, such as a
compound described in U.S. Pat. Nos. 6,727,251, 6,696,452,
6,664,247, 666,073, 6,656,939, 6,653,301, 6,653,300, 6,638,926,
6,613,776, or 6,610,677; or International Publication Nos.
WO-2005002552, WO-2005002576, or WO-2005012256; a compound
described in U.S. Pat. Nos. 6,719,520; 6,498,176; 6,800,632; or
6,872,737; U.S. Publication Nos. 20050137201; 20050176713;
20050004125; 20040010031; 20030105075; 20030008866; 20010044436;
20040138273; or 20040214928; International Publication Nos. WO
99/21859; WO-00210158; WO-05051919; WO-00232896; WO-2004046117;
WO-2004106343; WO-00210141; WO-00218346; WO 00/21927; WO 01/81345;
WO 01/74771; WO 05/028475; WO 01/09106; WO 00/21927; W001/41768; WO
00/17184; WO 04/037791; WO-04065370; WO 01/37819; WO 01/42224; WO
01/85685; WO 04/072063; WO-2004085439; WO-2005000303;
WO-2005000304; or WO 99/47522; or Naerum, L., et al., Bioorg. Med.
Chem. Lett. 12, 1525 (2002); CP-79049, GI 179186X, GW 784752X, GW
784775X, AZD-1080, AR-014418, SN-8914, SN-3728, TDZD-8, OTDZT,
Aloisine A, TWS119, CHIR98023, CHIR99021, CHIR98014, CHIR98023,
5-iodotubercidin, Ro 31-8220, SB-216763, SB-410111, SB-495052,
SB-415286, alsterpaullone, kenpaullone, gwennpaullone, LY294002,
wortmannin, sildenafil, CT98014, CT-99025, flavoperidol, or
L803-mts.
[0166] In yet further embodiments, the neurogenic agent used in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be a reported glutamate modulator. In some
embodiments, the reported mGlu receptor modulator is a Group II
modulator, having activity against one or more Group II receptors
(mGlu.sub.2 and/or mGlu.sub.3). Embodiments include those where the
Group II modulator is a Group II agonist. Non-limiting xamples of
Group II agonists include: (i)
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a broad
spectrum mGlu agonist having substantial activity at Group I and II
receptors; (ii) (-)-2-thia-4-aminobicyclo-hexane-4,6-dicarboxylate
(LY389795), which is described in Monn et al., J. Med. Chem.,
42(6):1027-40 (1999); (iii) compounds described in US App. No.
20040102521 and Pellicciari et al., J. Med. Chem., 39, 2259-2269
(1996); and (iv) the Group II-specific modulators described
below.
[0167] Non-limiting examples of reported Group II antagonists
include: (i) phenylglycine analogues, such as
(RS)-alpha-methyl-4-sulphonophenylglycine (MSPG),
(RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), and
(RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), described in
Jane et al., Neuropharmacology 34: 851-856 (1995); (ii) LY366457,
which is described in O'Neill et al., Neuropharmacol., 45(5):
565-74 (2003); (iii) compounds described in US App Nos.
20050049243, 20050119345 and 20030157647; and (iv) the Group
II-specific modulators described below.
[0168] In some non-limiting embodiments, the reported Group II
modulator is a Group II-selective modulator, capable of modulating
mGlu.sub.2 and/or mGlu.sub.3 under conditions where it is
substantially inactive at other mGlu subtypes (of Groups I and
III). Examples of Group II--selective modulators include compounds
described in Monn, et al., J. Med. Chem., 40, 528-537 (1997);
Schoepp, et al., Neuropharmacol., 36, 1-11 (1997) (e.g.,
1S,2S,5R,6S-2-aminobicyclohexane-2,6-dicarboxylate); and Schoepp,
Neurochem. Int., 24, 439 (1994).
[0169] Non-limiting examples of reported Group II-selective
agonists include (i) (+)-2-aminobicyclohexane-2,6-dicarboxylic acid
(LY354740), which is described in Johnson et al., Drug Metab.
Disposition, 30(1): 27-33 (2002) and Bond et al., NeuroReport 8:
1463-1466 (1997), and is systemically active after oral
administration (e.g., Grillon et al., Psychopharmacol. (Berl), 168:
446-454 (2003)); (ii)
(-)-2-Oxa-4-aminobicyclohexane-4,6-dicarboxylic acid (LY379268),
which is described in Monn et al., J. Med. Chem. 42: 1027-1040
(1999) and U.S. Pat. No. 5,688,826. LY379268 is readily permeable
across the blood-brain barrier, and has EC.sub.50 values in the low
nanomolar range (e.g., below about 10 nM, or below about 5 nM)
against human mGlu.sub.2 and mGlu.sub.3 receptors in vitro; (iii)
(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), which
is described in Monn et al., J. Med. Chem. 39: 2990 (1996) and
Schoepp et al., Neuropharmacology, 38: 1431 (1999); (iv)
(1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3S)-ACPD),
described in Schoepp, Neurochem. Int., 24: 439 (1994); (v)
(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid ((2R,4R)-APDC),
described in Howson and Jane, British Journal of Pharmacology, 139,
147-155 (2003); (vi) (2S,1'S,2'S)-2-(carboxycyclopropyl)-glycine
(L-CCG-I), described in Brabet et al., Neuropharmacology 37:
1043-1051 (1998); (vii)
(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV),
described in Hayashi et al., Nature, 366, 687-690 (1993); (viii)
1S,2S,5R,6S-2-aminobicyclohexane-2,6-dicarboxylate, described in
Monn, et al., J. Med. Chem., 40, 528 (1997) and Schoepp, et al.,
Neuropharmacol., 36, 1 (1997); and (vii) compounds described in US
App. No. 20040002478; U.S. Pat. Nos. 6,204,292, 6,333,428,
5,750,566 and 6,498,180; and Bond et al., Neuroreport 8: 1463-1466
(1997).
[0170] Non-limiting examples of reported Group II-selective
antagonists useful in methods provided herein include the
competitive antagonist
(2S)-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic
acid (LY341495), which is described, e.g., in Kingston et al.,
Neuropharmacology 37: 1-12 (1998) and Monn et al., J Med Chem 42:
1027-1040 (1999). LY341495 is readily permeably across the
blood-brain barrier, and has IC.sub.50 values in the low nanomolar
range (e.g., below about 10 nM, or below about 5 nM) against cloned
human mGlu.sub.2 and mGlu.sub.3 receptors. LY341495 has a high
degree of selectivity for Group II receptors relative to Group I
and Group III receptors at low concentrations (e.g., nanomolar
range), whereas at higher concentrations (e.g., above 1 .mu.M),
LY341495 also has antagonist activity against mGlu.sub.7 and
mGlu.sub.8, in addition to mGlu.sub.2/3. LY341495 is substantially
inactive against KA, AMPA, and NMDA iGlu receptors.
[0171] Additional non-limiting examples of reported Group
II-selective antagonists include the following compounds, indicated
by chemical name and/or described in the cited references: (i)
x-methyl-L-(carboxycyclopropyl) glycine (CCG); (ii)
(2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG); (iii)
(1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6
fluorobicyclohexane-2,6-dicarboxylic acid (MGS0039), which is
described in Nakazato et al., J. Med. Chem., 47(18):4570-87 (2004);
(iv) an n-hexyl, n-heptyl, n-octyl, 5-methylbutyl, or
6-methylpentyl ester prodrug of MGS0039; (v) MGS0210
(3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclohexane-2,6-dicarboxylic
acid n-heptyl ester); (vi)
(RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA), which is
described in Ma et al., Bioorg. Med. Chem. Lett., 7: 1195 (1997);
(vii) (2S)-ethylglutamic acid (EGLU), which is described in Thomas
et al., Br. J. Pharmacol. 117: 70P (1996); (viii)
(2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine
(PCCG-IV); and (ix) compounds described in U.S. Pat. No. 6,107,342
and US App No. 20040006114. APICA has an IC.sub.50 value of
approximately 30 .mu.M against mGluR.sub.2 and mGluR.sub.3, with no
appreciable activity against Group I or Group III receptors at
sub-mM concentrations.
[0172] In some non-limiting embodiments, a reported Group
II-selective modulator is a subtype-selective modulator, capable of
modulating the activity of mGlu.sub.2 under conditions in which it
is substantially inactive at mGlu.sub.3 (mGlu.sub.2-selective), or
vice versa (mGlu.sub.3-selective). Non-limiting examples of
subtype-selective modulators include compounds described in U.S.
Pat. No. 6,376,532 (mGlu.sub.2-selective agonists) and US App No.
20040002478 (mGlu.sub.3-selective agonists). Additional
non-limiting examples of subtype-selective modulators include
allosteric mGlu receptor modulators (mGlu.sub.2 and mGlu.sub.3) and
NAAG-related compounds (mGlu.sub.3), such as those described
below.
[0173] In other non-limiting embodiments, a reported Group II
modulator is a compound with activity at Group I and/or Group III
receptors, in addition to Group II receptors, while having
selectivity with respect to one or more mGlu receptor subtypes.
Non-limiting examples of such compounds include: (i)
(2S,3S,4S)-2-(carboxycyclopropyl)glycine (L-CCG-1) (Group I/Group
II agonist), which is described in Nicoletti et al., Trends
Neurosci. 19: 267-271 (1996), Nakagawa, et al., Eur. J. Pharmacol.,
184, 205 (1990), Hayashi, et al., Br. J. Pharmacol., 107, 539
(1992), and Schoepp et al., J. Neurochem., 63., page 769-772
(1994); (ii) (S)-4-carboxy-3-hydroxyphenylglycine (4C.sub.3HPG)
(Group II agonist/Group I competitive antagonist); (iii)
gamma-carboxy-L-glutamic acid (GLA) (Group II antagonist/Group III
partial agonist/antagonist); (iv)
(2S,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (Group II
agonist/Group III antagonist), which is described in Ohfune et al,
Bioorg. Med. Chem. Lett., 3: 15 (1993); (v)
(RS)-a-methyl-4-carboxyphenylglycine (MCPG) (Group I/Group II
competitive antagonist), which is described in Eaton et al., Eur.
J. Pharmacol., 244: 195 (1993), Collingridge and Watkins, TiPS, 15:
333 (1994), and Joly et al., J. Neurosci., 15: 3970 (1995); and
(vi) the Group II/III modulators described in U.S. Pat. Nos.
5,916,920, 5,688,826, 5,945,417, 5,958,960, 6,143,783, 6,268,507,
6,284,785.
[0174] In some non-limiting embodiments, the reported mGlu receptor
modulator comprises (S)-MCPG (the active isomer of the Group
I/Group II competitive antagonist (RS)-MCPG) substantially free
from (R)-MCPG. (S)-MCPG is described, e.g., in Sekiyama et al., Br.
J. Pharmacol., 117: 1493 (1996) and Collingridge and Watkins, TiPS,
15: 333 (1994).
[0175] Additional non-limiting examples of reported mGlu modulators
useful in methods disclosed herein include compounds described in
U.S. Pat. Nos. 6,956,049, 6,825,211, 5,473,077, 5,912,248,
6,054,448, and 5,500,420; US App Nos. 20040077599, 20040147482,
20040102521, 20030199533 and 20050234048; and Intl Pub/App Nos. WO
97/19049, WO 98/00391, and EP0870760.
[0176] In some non-limiting embodiments, the reported mGlu receptor
modulator is a prodrug, metabolite, or other derivative of
N-Acetylaspartylglutamate (NAAG), a peptide neurotransmitter in the
mammalian CNS that is a highly selective agonist for mGluR.sub.3
receptors, as described in Wroblewska et al., J. Neurochem., 69(1):
174-181 (1997). In other embodiments, the mGlu modulator is a
compound that modulates the levels of endogenous NAAG, such as an
inhibitor of the enzyme N-acetylated-alpha-linked-acidic
dipeptidase (NAALADase), which catalyzes the hydrolysis of NAAG to
N-acetyl-aspartate and glutamate. Examples of NAALADase inhibitors
include 2-PMPA (2-(phosphonomethyl)pentanedioic acid), which is
described in Slusher et al,, Nat. Med., 5(12): 1396-402 (1999); and
compounds described in J. Med. Chem. 39: 619 (1996), US Pub. No.
20040002478, and U.S. Pat. Nos. 6,313,159, 6,479,470, and
6,528,499. In some embodiments, the mGlu modulator is the
mGlu.sub.3-selective antagonist, beta-NAAG.
[0177] Additional non-limiting examples of reported glutamate
modulators include memantine (CAS RN 19982-08-2), memantine
hydrochloride (CAS RN 41100-52-1), and riluzole (CAS RN
1744-22-5).
[0178] In some non-limiting embodiments, a reported Group II
modulator is administered in combination with one or more
additional compounds reported as active against a Group I and/or a
Group III mGlu receptor. For example, in some cases, methods
comprise modulating the activity of at least one Group I receptor
and at least one Group II mGlu receptor (e.g., with a compound
described herein). Examples of compounds useful in modulating the
activity of Group I receptors include Group I-selective agonists,
such as (i) trans-azetidine-2,4,-dicarboxylic acid (tADA), which is
described in Kozikowski et al., J. Med. Chem., 36: 2706 (1993) and
Manahan-Vaughan et al., Neuroscience, 72: 999 (1996); (ii)
(RS)-3,5-Dihydroxyphenylglycine (DHPG), which is described in Ito
et al., NeuroReport 3: 1013 (1992); or a composition comprising
(S)-DHPG substantially free of (R)-DHPG, as described, e.g., in
Baker et al., Bioorg. Med. Chem. Lett. 5: 223 (1995); (iii)
(RS)-3-Hydroxyphenylglycine, which is described in Birse et al.,
Neuroscience 52: 481 (1993); or a composition comprising
(S)-3-Hydroxyphenylglycine substantially free of
(R)-3-Hydroxyphenylglycine, as described, e.g., in Hayashi et al,,
J. Neurosci., 14: 3370 (1994); (iv) and (S)-Homoquisqualate, which
is described in Porter et al., Br. J. Pharmacol., 106: 509
(1992),
[0179] Additional non-limiting examples of reported Group I
modulators include (i) Group I agonists, such as
(RS)-3,5-dihydroxyphenylglycine, described in Brabet et al.,
Neuropharmacology, 34, 895-903, 1995; and compounds described in
U.S. Pat. Nos. 6,399,641 and 6,589,978, and US Pub No. 20030212066;
(ii) Group I antagonists, such as
(S)-4-Carboxy-3-hydroxyphenylglycine;
7-(Hydroxyimino)cyclopropa-.beta.-chromen-1.alpha.-carboxylate
ethyl ester; (RS)-1-Aminoindan-1,5-dicarboxylic acid (AIDA);
2-Methyl-6 (phenylethynyl)pyridine (MPEP);
2-Methyl-6-(2-phenylethenyl)pyridine (SIB-1893);
6-Methyl-2-(phenylazo)-3-pyridinol (SIB-1757);
(S.alpha.-Amino-4-carboxy-2-methylbenzeneacetic acid; and compounds
described in U.S. Pat. Nos. 6,586,422, 5,783,575, 5,843,988,
5,536,721, 6,429,207, 5,696,148, and 6,218,385, and US Pub Nos.
20030109504, 20030013715, 20050154027, 20050004130, 20050209273,
20050197361, and 20040082592; (iii) mGlu.sub.5-selective agonists,
such as (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG); and (iv)
mGlu.sub.5-selective antagonists, such as
2-methyl-6-(phenylethynyl)-pyridine (MPEP); and compounds described
in U.S. Pat. No. 6,660,753; and US Pub Nos. 20030195139,
20040229917, 20050153986, 20050085514, 20050065340, 20050026963,
20050020585, and 20040259917.
[0180] Non-limiting examples of compounds reported to modulate
Group III receptors include (i) the Group III-selective agonists
(L)-2-amino-4-phosphonobutyric acid (L-AP4), described in Knopfel
et al., J. Med Chem., 38, 1417-1426 (1995); and
(S)-2-Amino-2-methyl-4-phosphonobutanoic acid; (ii) the Group
III-selective antagonists
(RS)-.alpha.-Cyclopropyl-4-phosphonophenylglycine;
(RS)-.alpha.-Methylserine-O-phosphate (MSOP); and compounds
described in US App. No. 20030109504; and (iii)
(1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid
(ACPT-I).
[0181] In additional embodiments, the neurogenic agent used in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be an AMPA modulator. Non-limiting examples include
CX-516 or ampalex (CAS RN 154235-83-3), Org-24448 (CAS RN
211735-76-1), LY451395 (2-propanesulfonamide,
N-[(2R)-2-[4'-[2-[methylsulfonyl)amino]ethyl][1,1'-biphenyl]-4-yl]propyl]-
-), LY-450108 (see Jhee et al. "Multiple-dose plasma
pharmacokinetic and safety study of LY450108 and LY451395 (AMPA
receptor potentiators) and their concentration in cerebrospinal
fluid in healthy human subjects." J Clin Pharmacol. 2006
46(4):424-32), and CX717. Additional examples of reported
antagonists include irampanel (CAS RN 206260-33-5) and E-2007.
[0182] Further non-limiting examples of reported AMPA receptor
antagonists for use in combinations include YM90K (CAS RN
154164-30-4), YM872 or Zonampanel (CAS RN 210245-80-0), NBQX (or
2,3-Dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; CAS RN
118876-58-7), PNQX
(1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3,
4-f]quinoxaline-2,3-dione), and ZK200775
([1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(fluoromethyl)quinoxalin-1-
-yl]methylphosphonate).
[0183] In yet additional embodiments, the neurogenic agent in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, is a reported HDAC inhibitor. The term "HDAC" refers to
any one of a family of enzymes that remove acetyl groups from the
epsilon-amino groups of lysine residues at the N-terminus of a
histone. An HDAC inhibitor refers to compounds capable of
inhibiting, reducing, or otherwise modulating the deacetylation of
histones mediated by a histone deacetylase. Non-limiting examples
of a reported HDAC inhibitor include a short-chain fatty acid, such
as butyric acid, phenylbutyrate (PB), 4-phenylbutyrate (4-PBA),
pivaloyloxymethyl butyrate (Pivanex, AN-9), isovalerate, valerate,
valproate, valproic acid, propionate, butyramide, isobutyramide,
phenylacetate, 3-bromopropionate, or tributyrin; a compound bearing
a hydroxyamic acid group, such as suberoylanlide hydroxamic acid
(SAHA), trichostatin A (TSA), trichostatin C (TSC),
salicylhydroxamic acid, oxamflatin, suberic bishydroxamic acid
(SBHA), m-carboxy-cinnamic acid bishydroxamic acid (CBHA),
pyroxamide (CAS RN 382180-17-8), diethyl
bis-(pentamethylene-N,N-dimethylcarboxamide)malonate (EMBA),
azelaic bishydroxamic acid (ABHA), azelaic-1-hydroxamate-9-anilide
(AAHA), 6-(3-Chlorophenylureido) carpoic hydroxamic acid, or
A-161906; a cyclic tetrapeptide, such as Depsipeptide (FK228),
FR225497, trapoxin A, apicidin, chlamydocin, or HC-toxin; a
benzamide, such as MS-275; depudecin, a sulfonamide anilide (e.g.,
diallyl sulfide), BL1521, curcumin (diferuloylmethane), CI-994
(N-acetyldinaline), spiruchostatin A, Scriptaid, carbamazepine
(CBZ), or a related compound; a compound comprising a cyclic
tetrapeptide group and a hydroxamic acid group (examples of such
compounds are described in U.S. Pat. Nos. 6,833,384 and 6,552,065);
a compound comprising a benzamide group and a hydroxamic acid group
(examples of such compounds are described in Ryu et al., Cancer
Lett. 2005 Jul. 9 (epub), Plumb et al., Mol Cancer Ther.,
2(8):721-8 (2003), Ragno et al., J Med Chem., 47(6):1351-9 (2004),
Mai et al., J Med Chem., 47(5):1098-109 (2004), Mai et al., J Med
Chem., 46(4):512-24 (2003), Mai et al., J Med Chem., 45(9):1778-84
(2002), Massa et al., J Med Chem., 44(13):2069-72 (2001), Mai et
al., J Med Chem., 48(9):3344-53 (2005), and Mai et al., J Med
Chem., 46(23):4826-9 (2003)); a compound described in U.S. Pat.
Nos. 6,897,220, 6,888,027, 5,369,108, 6,541,661, 6,720,445,
6,562,995, 6,777,217, or 6,387,673, or U.S. Patent Publication Nos.
20050171347, 20050165016, 20050159470, 20050143385, 20050137234,
20050137232, 20050119250, 20050113373, 20050107445, 20050107384,
20050096468, 20050085515, 20050032831, 20050014839, 20040266769,
20040254220, 20040229889, 20040198830, 20040142953, 20040106599,
20040092598, 20040077726, 20040077698, 20040053960, 20030187027,
20020177594, 20020161045, 20020119996, 20020115826, 20020103192, or
20020065282; FK228, AN-9, MS-275, CI-994, SAHA, G2M-777, PXD-101,
LBH-589, MGCD-0103, MK0683, sodium phenylbutyrate, CRA-024781, and
derivatives, salts, metabolites, prodrugs, and stereoisomers
thereof; and a molecule that inhibits the transcription and/or
translation of one or more HDACs.
[0184] Additional non-limiting examples include a reported HDac
inhibitor selected from ONO-2506 or arundic acid (CAS RN
185517-21-9); MGCD0103 (see Gelmon et al. "Phase I trials of the
oral histone deacetylase (HDAC) inhibitor MGCD0103 given either
daily or 3.times. weekly for 14 days every 3 weeks in patients
(pts) with advanced solid tumors." Journal of Clinical Oncology,
2005 ASCO Annual Meeting Proceedings. 23(16S, June 1 Supplement),
2005: 3147 and Kalita et al. "Pharmacodynamic effect of MGCD0103,
an oral isotype-selective histone deacetylase (HDAC) inhibitor, on
HDAC enzyme inhibition and histone acetylation induction in Phase I
clinical trials in patients (pts) with advanced solid tumors or
non-Hodgkin's lymphoma (NHL)" Journal of Clinical Oncology, 2005
ASCO Annual Meeting Proceedings. 23(16S, Part I of II, June 1
Supplement), 2005: 9631), a reported thiophenyl derivative of
benzamide HDac inhibitor as presented at the 97th American
Association for Cancer Research (AACR) Annual Meeting in
Washington, D.C. in a poster titled "Enhanced Isotype-Selectivity
and Antiproliferative Activity of Thiophenyl Derivatives of
BenzamideHDAC Inhibitors In Human Cancer Cells," (abstract #4725),
and a reported HDac inhibitor as described in U.S. Pat. No.
6,541,661; SAHA or Vorinostat (CAS RN 149647-78-9); PXD101 or PXD
101 or PX 105684 (CAS RN 414864-00-9), CI-994 or Tacedinaline (CAS
RN 112522-64-2), MS-275 (CAS RN 209783-80-2), or an inhibitor
reported in WO2005/108367.
[0185] In other embodiments, the neurogenic agent in combination
with a muscarinic agent, such as an inhibitor of AChE activity, is
a reported GABA modulator which modulates GABA receptor activity at
the receptor level (e.g., by binding directly to GABA receptors),
at the transcriptional and/or translational level (e.g., by
preventing GABA receptor gene expression), and/or by other modes
(e.g., by binding to a ligand or effector of a GABA receptor, or by
modulating the activity of an agent that directly or indirectly
modulates GABA receptor activity). Non-limiting examples of GABA-A
receptor modulators useful in methods described herein include
triazolophthalazine derivatives, such as those disclosed in WO
99/25353, and WO/98/04560; tricyclic pyrazolo-pyridazinone
analogues, such as those disclosed in WO 99/00391; fenamates, such
as those disclosed in 5,637,617; triazolo-pyridazine derivatives,
such as those disclosed in WO 99/37649, WO 99/37648, and WO
99/37644; pyrazolo-pyridine derivatives, such as those disclosed in
WO 99/48892; nicotinic derivatives, such as those disclosed in WO
99/43661 and U.S. Pat. No. 5,723,462; muscimol, thiomuscimol, and
compounds disclosed in U.S. Pat. No. 3,242,190; baclofen and
compounds disclosed in U.S. Pat. No. 3,471,548; phaclofen;
quisqualamine; ZAPA; zaleplon; THIP; imidazole-4-acetic acid (IMA);
(+)-bicuculline; gabalinoleamide; isoguvicaine; 3-aminopropane
sulphonic acid; piperidine-4-sulphonic acid;
4,5,6,7-tetrahydro-[5,4-c]-pyridin-3-01; SR 95531; RU5315; CGP
55845; CGP 35348; FG 8094; SCH 50911; NG2-73; NGD-96-3; pricrotoxin
and other bicyclophosphates disclosed in Bowery et al., Br. J.
Pharmacol., 57; 435 (1976).
[0186] The combination of the muscarinic agent tacrine with
baclofen resulted in synergistic activity (see Example 8 below).
See also Example 12 for a discussion of synergy. Tacrine alone has
an EC.sub.50 of 8.0 uM for neuronal differentiation. Baclofen alone
has an EC.sub.50 of 3.6 .mu.M. The concentration of each agent in
combination to reach 50% activity in neuronal differentiation is
1.8 .mu.M, resulting in a CI of 0.84. As the CI is less than 1, the
two compounds have a synergistic effect in neuronal
differentiation.
[0187] Additional non-limiting examples of GABA-A modulators
include compounds described in U.S. Pat. Nos. 6,503,925; 6,218,547;
6,399,604; 6,646,124; 6,515,140; 6,451,809; 6,448,259; 6,448,246;
6,423,711; 6,414,147; 6,399,604; 6,380,209; 6,353,109; 6,297,256;
6,297,252; 6,268,496; 6,211,365; 6,166,203; 6,177,569; 6,194,427;
6,156,898; 6,143,760; 6,127,395; 6,103,903; 6,103,731; 6,723,735;
6,479,506; 6,476,030; 6,337,331; 6,730,676; 6,730,681; 6,828,322;
6,872,720; 6,699,859; 6,696,444; 6,617,326; 6,608,062; 6,579,875;
6,541,484; 6,500,828; 6,355,798; 6,333,336; 6,319,924; 6,303,605;
6,303,597; 6,291,460; 6,255,305; 6,133,255; 6,872,731; 6,900,215;
6,642,229; 6,593,325; 6,914,060; 6,914,063; 6,914,065; 6,936,608;
6,534,505; 6,426,343; 6,313,125; 6,310,203; 6,200,975; 6,071,909;
5,922,724; 6,096,887; 6,080,873; 6,013,799; 5,936,095; 5,925,770;
5,910,590; 5,908,932; 5,849,927; 5,840,888; 5,817,813; 5,804,686;
5,792,766; 5,750,702; 5,744,603; 5,744,602; 5,723,462; 5,696,260;
5,693,801; 5,677,309; 5,668,283; 5,637,725; 5,637,724; 5,625,063;
5,610,299; 5,608,079; 5,606,059; 5,604,235; 5,585,490; 5,510,480;
5,484,944; 5,473,073; 5,463,054; 5,451,585; 5,426,186; 5,367,077;
5,328,912; 5,326,868; 5,312,822; 5,306,819; 5,286,860; 5,266,698;
5,243,049; 5,216,159; 5,212,310; 5,185,446; 5,185,446; 5,182,290;
5,130,430; 5,095,015; 20050014939; 20040171633; 20050165048;
20050165023; 20040259818; and 20040192692.
[0188] In some embodiments, the GABA-A modulator is a
subunit-selective modulator. Non-limiting examples of GABA-A
modulator having specificity for the alphal subunit include alpidem
and zolpidem. Non-limiting examples of GABA-A modulator having
specificity for the alpha2 and/or alpha3 subunits include compounds
described in U.S. Pat. Nos. 6,730,681; 6,828,322; 6,872,720;
6,699,859; 6,696,444; 6,617,326; 6,608,062; 6,579,875; 6,541,484;
6,500,828; 6,355,798; 6,333,336; 6,319,924; 6,303,605; 6,303,597;
6,291,460; 6,255,305; 6,133,255; 6,900,215; 6,642,229; 6,593,325;
and 6,914,063. Non-limiting examples of GABA-A modulator having
specificity for the alpha2, alpha3 and/or alpha5 subunits include
compounds described in U.S. Pat. Nos. 6,730,676 and 6,936,608.
Non-limiting examples of GABA-A modulators having specificity for
the alpha5 subunit include compounds described in U.S. Pat. Nos.
6,534,505; 6,426,343; 6,313,125; 6,310,203; 6,200,975 and
6,399,604. Additional non-limiting subunit selective GABA-A
modulators include CL218,872 and related compounds disclosed in
Squires et al., Pharmacol. Biochem. Behay., 10: 825 (1979); and
beta-carboline-3-carboxylic acid esters described in Nielsen et
al., Nature, 286: 606 (1980).
[0189] In some embodiments, the GABA-A receptor modulator is a
reported allosteric modulator. In various embodiments, allosteric
modulators modulate one or more aspects of the activity of GABA at
the target GABA receptor, such as potency, maximal effect,
affinity, and/or responsiveness to other GABA modulators. In some
embodiments, allosteric modulators potentiate the effect of GABA
(e.g., positive allosteric modulators), and/or reduce the effect
of
[0190] GABA (e.g., inverse agonists). Non-limiting examples of
benzodiazepine GABA-A modulators include aiprazolam, bentazepam,
bretazenil, bromazepam, brotizolam, cannazepam, chlordiazepoxide,
clobazam, clonazepam, cinolazepam, clotiazepam, cloxazolam,
clozapin, delorazepam, diazepam, dibenzepin, dipotassium
chlorazepat, divaplon, estazolam, ethyl-loflazepat, etizolam,
fludiazepam, flumazenil, flunitrazepam, flurazepamI 1HCl,
flutoprazepam, halazeparn, haloxazolam, imidazenil, ketazolam,
lorazepam, loprazolam, lormetazepam, medazepam, metaclazepam,
mexozolam, midazolam-HCl, nabanezil, nimetazepam, nitrazepam,
nordazepam, oxazepam-tazepam, oxazolam, pinazepam, prazepam,
quazepam, sarmazenil, suriclone, temazepam, tetrazepam, tofisopam,
triazolam, zaleplon, zolezepam, zolpidem, zopiclone, and
zopielon.
[0191] Additional non-limiting examples of benzodiazepine GABA-A
modulators include Ro15-4513, CL218872, CGS 8216, CGS 9895, PK
9084, U-93631, beta-CCM, beta-CCB, beta-CCP, Ro 19-8022, CGS 20625,
NNC 14-0590, Ru 33-203, 5-amino-1-bromouracil, GYKI-52322, FG 8205,
Ro 19-4603, ZG-63, RWJ46771, SX-3228, and L-655,078; NNC 14-0578,
NNC 14-8198, and additional compounds described in Wong et al., Eur
J Pharmacol 209: 319-325 (1995); Y-23684 and additional compounds
in Yasumatsu et al., Br J Pharmacol 111: 1170-1178 (1994); and
compounds described in U.S. Pat. No. 4,513,135.
[0192] Non-limiting examples of barbiturate or barbituric acid
derivative GABA-A modulators include phenobarbital, pentobarbital,
pentobarbitone, primidone, barbexaclon, dipropyl barbituric acid,
eunarcon, hexobarbital, mephobarbital, methohexital,
Na-methohexital, 2,4,6(1H,3H,5)-pyrimidintrion, secbutabarbital
and/or thiopental.
[0193] Non-limiting examples of neurosteroid GABA-A modulators
include alphaxalone, allotetrahydrodeoxycorticosterone,
tetrahydrodeoxycorticosterone, estrogen, progesterone
3-beta-hydroxyandrost-5-en-17-on-3-sulfate, dehydroepianrosterone,
eltanolone, ethinylestradiol, 5-pregnen-3-beta-ol-20 on-sulfate,
5a-pregnan-3.alpha.-ol-20-one (5PG), allopregnanolone,
pregnanolone, and steroid derivatives and metabolites described in
U.S. Pat. Nos. 5,939,545, 5,925,630, 6,277,838, 6,143,736,
RE35,517, 5,925,630, 5,591,733, 5,232,917, 20050176976, WO
96116076, WO 98/05337, WO 95/21617, WO 94/27608, WO 93/18053, WO
93/05786, WO 93/03732, WO 91116897, EP01038880, and Han et al., J.
Med. Chem., 36, 3956-3967 (1993), Anderson et al., J. Med. Chem.,
40, 1668-1681 (1997), Hogenkamp et al., J. Med. Chem., 40, 61-72
(1997), Upasani et al., J. Med. Chem., 40, 73-84 (1997), Majewska
et al., Science 232:1004-1007 (1986), Harrison et al., J.
Pharmacol. Exp. Ther. 241:346-353 (1987), Gee et al., Eur. J.
Pharmacol., 136:419-423 (1987) and Birtran et al., Brain Res., 561,
157-161 (1991).
[0194] Non-limiting examples of beta-carboline GABA-A modulators
include abecarnil, 3,4-dihydro-beta-carboline, gedocarnil,
1-methyl-1-vinyl-2,3,4-trihydro-beta-carboline-3-carboxylic acid,
6-methoxy-1,2,3,4-tetrahydro-beta-carboline,
N-BOC-L-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid,
tryptoline, pinoline, methoxyharmalan, tetrahydro-beta-carboline
(THBC), 1-methyl-THBC, 6-methoxy-THBC, 6-hydroxy-THBC,
6-methoxyharmalan, norharman, 3,4-dihydro-beta-carboline, and
compounds described in Nielsen et al., Nature, 286: 606 (1980).
[0195] In some embodiments, the GABA modulator modulates GABA-B
receptor activity. Non-limiting examples of reported GABA-B
receptor modulators useful in methods described herein include
CGP36742; CGP-64213; CGP 56999A; CGP 54433A; CGP 36742; SCH 50911;
CGP 7930; CGP 13501; baclofen and compounds disclosed in U.S. Pat.
No. 3,471,548; saclofen; phaclofen; 2-hydroxysaclofen; SKF 97541;
CGP 35348 and related compounds described in Olpe, et al, Eur. J.
Pharmacol., 187, 27 (1990); phosphinic acid derivatives described
in Hills, et al, Br. J. Pharmacol., 102, pp. 5-6 (1991); and
compounds described in U.S. Pat. Nos. 4,656,298, 5,929,236,
EP0463969, EP 0356128, Kaupmann et al., Nature 368: 239 (1997),
Karla et al., J Med Chem., 42(11):2053-9 (1992), Ansar et al.,
Therapie, 54(5):651-8 (1999), and Castelli et al., Eur J
Pharmacol., 446(1-3):1-5 (2002).
[0196] In some embodiments, the GABA modulator modulates GABA-C
receptor activity. Non-limiting examples of reported GABA-C
receptor modulators useful in methods described herein include
cis-aminocrotonic acid (CACA); 1,2,5,6-tetrahydropyridine-4-yl
methyl phosphinic acid (TPMPA) and related compounds such as P4MPA,
PPA and SEPI; 2-methyl-TACA; (.+-.)-TAMP; muscimol and compounds
disclosed in U.S. Pat. No. 3,242,190; ZAPA; THIP and related
analogues, such as aza-THIP; pricotroxin; imidazole-4-acetic acid
(IMA); and CGP36742.
[0197] In some embodiments, the GABA modulator modulates the
activity of glutamic acid decarboxylase (GAD).
[0198] In some embodiments, the GABA modulator modulates GABA
transaminase (GTA). Non-limiting examples of GTA modulators include
the GABA analogue vigabatrin and compounds disclosed in U.S. Pat.
No. 3,960,927.
[0199] In some embodiments, the GABA modulator modulates the
reuptake and/or transport of GABA from extracellular regions. In
other embodiments, the GABA modulator modulates the activity of the
GABA transporters, GAT-1, GAT-2, GAT-3 and/or BGT-1. Non-limiting
examples of GABA reuptake and/or transport modulators include
nipecotic acid and related derivatives, such as CI 966; SKF 89976A;
TACA; stiripentol; tiagabine and GAT-1 inhibitors disclosed in U.S.
Pat. No. 5,010,090;
(R)-1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid and
related compounds disclosed in U.S. Pat. No. 4,383,999;
(R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic
acid and related compounds disclosed in Anderson et al., J. Med.
Chem. 36, (1993) 1716-1725; guvacine and related compounds
disclosed in Krogsgaard-Larsen, Molecular & Cellular
Biochemistry 31, 105-121 (1980); GAT-4 inhibitors disclosed in U.S.
Pat. No. 6,071,932; and compounds disclosed in U.S. Pat. No.
6,906,177 and Ali, F. E., et al. J. Med. Chem. 1985, 28, 653-660.
Methods for detecting GABA reuptake inhibitors are known in the
art, and are described, e.g., in U.S. Pat. Nos. 6,906,177;
6,225,115; 4,383,999; Ali, F. E., et al. J. Med. Chem. 1985, 28,
653-660.
[0200] In some embodiments, the GABA modulator is the
benzodiazepine Clonazepam, which is described, e.g., in U.S. Pat.
Nos. 3,121,076 and 3,116,203; the benzodiazepine Diazepam, which is
described, e.g., in U.S. Pat. Nos. 3,371,085; 3,109,843; and
3,136,815; the short-acting diazepam derivative Midazolam, which is
a described, e.g., in U.S. Pat. No. 4,280,957; the imidazodiazepine
Flumazenil, which is described, e.g., in U.S. Pat. No. 4,316,839;
the benzodiazepine Lorazepam is described, e.g., in U.S. Pat. No.
3,296,249; the benzodiazepine L-655708, which is described, e.g.,
in Quirk et al. Neuropharmacology 1996, 35, 1331; Sur et al. Mol.
Pharmacol, 1998, 54, 928; and Sur et al. Brain Res. 1999, 822, 265;
the benzodiazepine Gabitril; Zopiclone, which binds the
benzodiazepine site on GABA-A receptors, and is disclosed, e.g., in
U.S. Pat. Nos. 3,862,149 and 4,220,646.; the GABA-A potentiator
Indiplon as described, e.g., in Foster et al., J Pharmacol Exp
Ther., 311(2):547-59 (2004), U.S. Pat. Nos. 4,521,422 and
4,900,836; Zolpidem, described, e.g., in U.S. Pat. No. 4,794,185
and EP50563; Zaleplon, described, e.g., in U.S. Pat. No. 4,626,538;
Abecarnil, described, e.g., in Stephens et al., J Pharmacol Exp
Ther., 253(1):334-43 (1990); the GABA-A agonist Isoguvacine, which
is described, e.g., in Chebib et al., Clin. Exp. Pharmacol,
Physiol. 1999, 26, 937-940; Leinekugel et al. J. Physiol. 1995,
487, 319-29; and White et al., J. Neurochem. 1983, 40(6), 1701-8;
the GABA-A agonist Gaboxadol (THIP), which is described, e.g., in
U.S. Pat. No. 4,278,676 and Krogsgaard-Larsen, Acta. Chem. Scand.
1977, 31, 584; the GABA-A agonist Muscimol, which is described,
e.g., in U.S. Pat. Nos. 3,242,190 and 3,397,209; the inverse GABA-A
agonist beta-CCP, which is described, e.g., in Nielsen et al., J.
Neurochem., 36(1):276-85 (1981); the GABA-A potentiator Riluzole,
which is described, e.g., in U.S. Pat. No. 4,370,338 and EP 50,551;
the GABA-B agonist and GABA-C antagonist SKF 97541, which is
described, e.g., in Froestl et al., J. Med. Chem. 38 3297 (1995);
Hoskison et al., Neurosci. Lett. 2004, 365(1), 48-53 and Hue et
al., J. Insect Physiol. 1997, 43(12), 1125-1131; the GABA-B agonist
Baclofen, which is described, e.g., in U.S. Pat. No. 3,471,548; the
GABA-C agonist cis-4-aminocrotonic acid (CACA), which is described,
e.g., in Ulloor et al. J. Neurophysiol. 2004, 91(4), 1822-31; the
GABA-A antagonist Phaclofen, which is described, e.g., in Kerr et
al. Brain Res. 1987, 405, 150; Karlsson et al. Eur. J Pharmacol.
1988, 148, 485; and Hasuo, Gallagher Neurosci. Lett. 1988, 86, 77;
the GABA-A antagonist SR 95531, which is described, e.g., in Stell
et al. J. Neurosci. 2002, 22(10), RC223; Wermuth et al., J. Med.
Chem. 30 239 (1987); and Luddens and Korpi, J. Neurosci. 15: 6957
(1995); the GABA-A antagonist Bicuculline, which is a described,
e.g., in Groenewoud, J. Chem. Soc. 1936, 199; Olsen et al., Brain
Res. 102: 283 (1976) and Haworth et al. Nature 1950, 165, 529; the
selective GABA-B antagonist CGP 35348, which is described, e.g., in
Olpe et al. Eur. J. Pharmacol. 1990, 187, 27; Hao et al. Neurosci.
Lett. 1994, 182, 299; and Froestl et al. Pharmacol. Rev. Comm.
1996, 8, 127; the selective GABA-B antagonist CGP 46381, which is
described, e.g., in Lingenhoehl, Pharmacol. Comm. 1993, 3, 49; the
selective GABA-B antagonist CGP 52432, which is described, e.g., in
Lanza et al. Eur. J. Pharmacol. 1993, 237, 191; Froestl et al.
Pharmacol. Rev. Comm. 1996, 8, 127; Bonanno et al. Eur. J.
Pharmacol. 1998, 362, 143; and Libri et al. Naunyn-Schmied. Arch.
Pharmacol. 1998, 358, 168; the selective GABA-B antagonist CGP
54626, which is described, e.g., in Brugger et al. Eur. J.
Pharmacol. 1993, 235, 153; Froestl et al. Pharmacol. Rev. Comm.
1996, 8, 127; and Kaupmann et al. Nature 1998, 396, 683; the
selective GABA-B antagonist CGP 55845, which is a GABA-receptor
antagonist described, e.g., in Davies et al. Neuropharmacology
1993, 32, 1071; Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127;
and Deisz Neuroscience 1999, 93, 1241; the selective GABA-B
antagonist Saclofen, which is described, e.g., in Bowery, TiPS,
1989, 10, 401; and Kerr et al. Neurosci Lett. 1988;92(1):92-6; the
GABA-B antagonist 2-Hydroxysaclofen, which is described, e.g., in
Kerr et al. Neurosci. Lett. 1988, 92, 92; and Curtis et al.
Neurosci. Lett. 1988, 92, 97; the GABA-B antagonist SCH 50,911,
which is described, e.g., in Carruthers et al., Bioorg Med Chem
Lett 8: 3059-3064 (1998); Bolser et al. J. Pharmacol. Exp. Ther.
1996, 274, 1393; Hosford et al. J. Pharmacol. Exp. Ther. 1996, 274,
1399; and Ong et al. Eur. J. Pharmacol. 1998, 362, 35; the
selective GABA-C antagonist TPMPA, which is described, e.g., in
Schlicker et al., Brain Res. Bull. 2004, 63(2), 91-7; Murata et
al., Bioorg. Med. Chem. Lett. 6: 2073 (1996); and Ragozzino et al.,
Mol. Pharmacol. 50: 1024 (1996); a GABA derivative, such as
Pregabalin [(S)-(+)-3-isobutylgaba] or gabapentin
[1-(aminomethyl)cyclohexane acetic acid]. Gabapentin is described,
e.g., in U.S. Pat. No. 4,024,175; the lipid-soluble GABA agonist
Progabide, which is metabolized in vivo into GABA and/or
pharmaceutically active GABA derivatives in vivo. Progabide is
described, e.g., in U.S. Pat. Nos. 4,094,992 and 4,361,583; the
GAT1 inhibitor Tiagabine, which is described, e.g., in U.S. Pat.
No. 5,010,090 and Andersen et al. J. Med. Chem. 1993, 36, 1716; the
GABA transaminase inhibitor Valproic Acid (2-propylpentanoic acid
or dispropylacetic acid), which is described, e.g., in U.S. Pat.
No. 4,699,927 and Carraz et al., Therapie, 1965, 20, 419; the GABA
transaminase inhibitor Vigabatrin, which is described, e.g., in
U.S. Pat. No. 3,960,927; or Topiramate, which is described, e.g.,
in U.S. Pat. No. 4,513,006.
[0201] Additionally, the neurogenic agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
neurogenic sensitizing agent that is a reported anti-epileptic
agent. Non-limiting examples of such agents include carbamazepine
or tegretol (CAS RN 298-46-4), clonazepam (CAS RN 1622-61-3), BPA
or 3-(p-Boronophenyl)alanine (CAS RN 90580-64-6), gabapentin or
neurontin (CAS RN 60142-96-3), phenytoin (CAS RN 57-41-0),
topiramate, lamotrigine or lamictal (CAS RN 84057-84-1),
phenobarbital (CAS RN 50-06-6), oxcarbazepine (CAS RN 28721-07-5),
primidone (CAS RN 125-33-7), ethosuximide (CAS RN 77-67-8),
levetiracetam (CAS RN 102767-28-2), zonisamide, tiagabine (CAS RN
115103-54-3), depakote or divalproex sodium (CAS RN 76584-70-8),
Felbamate (Na-channel and NMDA receptor antagonist), or pregabalin
(CAS RN 148553-50-8).
[0202] In further embodiments, the neurogenic sensitizing agent may
be reported a direct or indirect modulator of dopamine receptors.
Non-limiting examples of such agents include the indirect dopamine
agonists methylphenidate (CAS RN 113-45-1) or Methylphenidate
hydrochloride (also known as ritalin CAS RN 298-59-9), amphetamine
(CAS RN 300-62-9) and methamphetamine (CAS RN 537-46-2), and the
direct dopamine agonists sumanirole (CAS RN 179386-43-7),
roprinirole (CAS RN 91374-21-9), and rotigotine (CAS RN
99755-59-6).
[0203] Additional non-limiting examples include bromocriptine (CAS
RN 25614-03-3), adrogolide (CAS RN 171752-56-0), pramipexole (CAS
RN 104632-26-0), Ropinirole (CAS RN 91374-21-9), apomorphine (CAS
RN 58-00-4) or apomorphine hydrochloride (CAS RN 314-19-2),
lisuride (CAS RN 18016-80-3), Sibenadet hydrochloride or Viozan
(CAS RN 154189-24-9), L-DOPA or Levodopa (CAS RN 59-92-7),
Melevodopa (CAS RN 7101-51-1), etilevodopa (CAS RN 37178-37-3),
Talipexole hydrochloride (CAS RN 36085-73-1) or Talipexole (CAS RN
101626-70-4), Nolomirole (CAS RN 90060-42-7), quinelorane (CAS RN
97466-90-5), pergolide (CAS RN 66104-22-1), fenoldopam (CAS RN
67227-56-9), Carmoxirole (CAS RN 98323-83-2), terguride (CAS RN
37686-84-3), cabergoline (CAS RN 81409-90-7), quinagolide (CAS RN
87056-78-8) or quinagolide hydrochloride (CAS RN 94424-50-7),
sumanirole, docarpamine (CAS RN 74639-40-0), SLV-308 or
2(3H)-Benzoxazolone, 7-(4-methyl-1-piperazinyl)-monohydrochloride
(CAS RN 269718-83-4), aripiprazole (CAS RN 129722-12-9),
bifeprunox, lisdexamfetamine dimesylate (CAS RN 608137-33-3),
safinamide (CAS RN 133865-89-1), or Adderall or Amfetamine (CAS RN
300-62-9).
[0204] The combination of the muscarinic agent tacrine with ritalin
resulted in at least additive activity (see Example 8 below). See
Example 12 for a discussion of additive activity. Tacrine alone has
an EC.sub.50 of 8.0 uM for neuronal differentiation. Ritalin alone
has an EC.sub.50 of 3.5 .mu.M. The concentration of each agent in
combination to reach 50% activity in neuronal differentiation is
2.06 .mu.M resulting in a CI of 0.9976. As the CI is less than 1,
the two compounds have at least an additive effect in neuronal
differentiation. This indicates that the administered amounts of
each compound can be lowered, with a concomitant reduction in side
effects profile, while still providing greater efficacy than either
compound alone.
[0205] In further embodiments, the neurogenic agent used in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be a reported dual sodium and calcium channel
modulator. Non-limiting examples of such agents include safinamide
and zonisamide. Additional non-limiting examples include enecadin
(CAS RN 259525-01-4), Levosemotiadil (CAS RN 116476-16-5),
bisaramil (CAS RN 89194-77-4), SL-34.0829 (see U.S. Pat. No.
6,897,305), lifarizine (CAS RN 119514-66-8), JTV-519
(4-[3-(4-benzylpiperidin-1-yepropionyl]-7-methoxy-2,3,4,5-tetrahy
dro-1,4-benzothiazepine monohydrochloride), and delapril.
[0206] In further embodiments, the neurogenic agent in used in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be a reported calcium channel antagonists such as
amlodipine (CAS RN 88150-42-9) or amlodipine maleate (CAS RN
88150-47-4), nifedipine (CAS RN 21829-25-4), MEM-1003 (CAS RN see
Rose et al, "Efficacy of MEM 1003, a novel calcium channel'blocker,
in delay and trace eyeblink conditioning in older rabbits."
Neurobiol Aging. 2006 Apr 16; [Epub ahead of print]), isradipine
(CAS RN 75695-93-1), felodipine (CAS RN 72509-76-3;
3,5-Pyridinedicarboxylic acid,
1,4-dihydro-4-(2,3-dichlorophenyl)-2,6-dimethyl-, ethyl methyl
ester) or felodipine (CAS RN 86189-69-7; 3,5-Pyridinedicarboxylic
acid, 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-, ethyl
methyl ester, (.+-.)-), lemildipine (CAS RN 125729-29-5 or
94739-29-4), clevidipine (CAS RN 166432-28-6 or 167221-71-8),
verapamil (CAS RN 52-53-9), ziconotide (CAS RN 107452-89-1),
monatepil maleate (CAS RN 132046-06-1), manidipine (CAS RN
89226-50-6), Furnidipine (CAS RN 138661-03-7), Nitrendipine (CAS RN
39562-70-4), Loperamide (CAS RN 53179-11-6), Amiodarone (CAS RN
1951-25-3), Bepridil (CAS RN 64706-54-3), diltiazem (CAS RN
42399-41-7), Nimodipine (CAS RN 66085-59-4), Lamotrigine,
Cinnarizine (CAS RN 298-57-7), lacipidine (CAS RN 103890-78-4),
nilvadipine (CAS RN 75530-68-6), dotarizine (CAS RN 84625-59-2),
cilnidipine (CAS RN 132203-70-4), Oxodipine (CAS RN 90729-41-2),
aranidipine (CAS RN 86780-90-7), anipamil (CAS RN 83200-10-6),
ipenoxazone (CAS RN 104454-71-9), Efonidipine hydrochloride or NZ
105 (CAS RN 111011-53-1) or Efonidipine (CAS RN 111011-63-3),
temiverine (CAS RN 173324-94-2), pranidipine (CAS RN 99522-79-9),
dopropidil (CAS RN 79700-61-1), lercanidipine (CAS RN 100427-26-7),
terodiline (CAS RN 15793-40-5), fantofarone (CAS RN 114432-13-2),
azelnidipine (CAS RN 123524-52-7), mibefradil (CAS RN 116644-53-2)
or mibefradil dihydrochloride (CAS RN 116666-63-8), SB-237376 (see
Xu et al. "Electrophysiologic effects of SB-237376: a new
antiarrhythmic compound with dual potassium and calcium channel
blocking action." J Cardiovasc Pharmacol, 2003 41(3):414-21),
BRL-32872 (CAS RN 113241-47-7), S-2150 (see Ishibashi et al.
"Pharmacodynamics of S-2150, a simultaneous calcium-blocking and
alphal-inhibiting antihypertensive drug, in rats." J Pharm
Pharmacol. 2000 52(3):273-80), nisoldipine (CAS RN 63675-72-9),
semotiadil (CAS RN 116476-13-2), palonidipine (CAS RN 96515-73-0)
or palonidipine hydrochloride (CAS RN 96515-74-1), SL-87.0495 (see
U.S. Pat. No. 6,897,305), YM430
(4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl
2,6-dimethyl-((S)-4-(m-nitrophenyl))-1,4-dihydropyridine-3,5-dicar-
boxylate), barnidipine (CAS RN 104713-75-9), and AM336 or CVID (see
Adams et al. "Omega-Conotoxin CVID Inhibits a Pharmacologically
Distinct Voltage-sensitive Calcium Channel Associated with
Transmitter Release from Preganglionic Nerve Terminals" J. Biol.
Chem., 278(6):4057-4062, 2003). An additional non-limiting example
is NMED-160.
[0207] In other embodiments, the neurogenic agent used in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be a reported modulator of a melatonin receptor.
Non-limiting examples of such modulators include the melatonin
receptor agonists melatonin, LY-156735 (CAS RN 118702-11-7),
agomelatine (CAS RN 138112-76-2), 6-chloromelatonin (CAS RN
63762-74-3), Ramelteon (CAS RN 196597-26-9),
2-Methyl-6,7-dichloromelatonin (CAS RN 104513-29-3), and ML 23 (CAS
RN 108929-03-9).
[0208] In yet further embodiments, the neurogenic agent in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be a reported modulator of a melanocortin receptor.
Non-limiting examples of such agents include a melanocortin
receptor agonists selected from melanotan II (CAS RN 121062-08-6),
PT-141 or Bremelanotide (CAS RN 189691-06-3), HP-228 (see Getting
et al. "The melanocortin peptide HP228 displays protective effects
in acute models of inflammation and organ damage." Eur J Pharmacol.
2006 Jan. 24), or AP214 from Action Pharma A/S.
[0209] Additional examples of combinations of a muscarinic agent,
such as an inhibitor of AChE activity, and another agent include
the muscarinic agent, ibudilast, and captopril; the muscarinic
agent, enoximone, and captopril; the muscarinic agent, enoximone,
and serotonin; the muscarinic agent, rolipram, and serotonin; and
the muscarinic agent, rolipram, and buspirone.
[0210] Thus a combination of neurogenic agents used with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of angiotensin II function, such as at an
angiotensin II receptor. In some embodiments, the neurogenic
sensitizing agent used with a muscarinic agent may be a reported
inhibitor of an angiotensin converting enzyme (ACE). Non-limiting
examples of such reported inhibitors include a
sulfhydryl-containing (or mercapto-containing) agent, such as
Alacepril, captopril (Capoten.RTM.), fentiapril, pivopril,
pivalopril, or zofenopril; a dicarboxylate-containing agent, such
as enalapril (Vasotec.RTM. or Renitec.RTM.) or enalaprilat,
ramipril (Altace.RTM. or Tritace.RTM. or Ramace.RTM.), quinapril
(Accupril.RTM.) or quinapril hydrochloride, perindopril
(Coversyl.RTM.) or perindopril erbumine (Aceon.RTM.), lisinopril
(Lisodur.RTM. or Prinivil.RTM. or Zestril.RTM.); a
phosphonate-containing (or phosphate-containing) agent, such as
fosinopril (Monopril.RTM.), fosinoprilat, fosinopril sodium (CAS RN
88889-14-9), benazepril (Lotensin.RTM.) or benazepril
hydrochloride, imidapril or imidapril hydrochloride, moexipril
(Univasc.RTM.), or trandolapril (Mavik.RTM.). In other embodiments,
a modulator is administered in the form of an ester that increases
biovavailability upon oral administration with subsequent
conversion into metabolites with greater activity.
[0211] Further embodiments include reported angiotensin II
modulating entities that are naturally occurring, such as
casokinins and lactokinins (breakdown products of casein and whey)
which may be administered as such to obviate the need for their
formation during digestion. Additional non-limiting embodiments of
reported angiotensin receptor antagonists include candesartan
(Atacand.RTM. or Ratacand.RTM., 139481-59-7) or candesartan
cilexetil; eprosartan (Teveten.RTM.) or eprosartan mesylate;
irbesartan (Aprovel.RTM. or Karvea.RTM. or Avapro.RTM.); losartan
(Cozaar.RTM. or Hyzaar.RTM.); olmesartan (Benicar.RTM., CAS RN
144689-24-7) or olmesartan medoxomil (CAS RN 144689-63-4);
telmisartan (Micardis.RTM. or Pritor.RTM.); or valsartan
(Diovan.RTM.).
[0212] Additional non-limiting examples of a reported angiotensin
modulator that may be used in a combination include nateglinide or
starlix (CAS RN 105816-04-4); tasosartan or its metabolite
enoltasosartan; omapatrilat (CAS RN 167305-00-2); or a a
combination of nateglinide and valsartan, amoldipine and benazepril
(Lotrel 10-40 or Lotrel 5-40), or delapril and manidipine (CHF
1521).
[0213] The combination of the muscarinic agent donepezil with
captopril resulted in synergistic activity (see Example 8 below).
Donepezil alone has an EC.sub.50 of 2.02 .mu.M for neuronal
differentiation. Captopril alone has an EC.sub.50 of 3.78 .mu.M.
The concentration of each agent in combination to reach 50%
activity in neuronal differentiation is 0.3 resulting in a CI of
0.24, As the CI is less than 1, the two compounds have a
synergistic effect in neuronal differentiation.
[0214] Additionally, the agent used with a muscarinic agent, such
as an inhibitor of AChE activity, may be a reported 5HT1a receptor
agonist (or partial agonist) such as buspirone (buspar). In some
embodiments, a reported 5HTla receptor agonist is an azapirone,
such as, but not limited to, tandospirone, gepirone and ipsapirone.
Non-limiting examples of additional reported 5HT1a receptor
agonists include flesinoxan, MDL 72832 hydrochloride, U-92016A,
(+)-UH 301, F 13714, F 13640, 6-hydroxy-buspirone (see US
2005/0137206), S-6-hydroxy-buspirone (see US 2003/0022899),
R-6-hydroxy-buspirone (see US 2003/0009851), adatanserin, and
buspirone-saccharide (see WO 00/12067). As indicated in Example 8
below, the combination of the muscarinic agent tacrine with
buspirone resulted in synergistic activity.
[0215] Additional non-limiting examples of reported 5HT1a receptor
agonists include OPC-14523
(1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1-
H]-quinolinone monomethanesulfonate); BMS-181100 or BMY 14802 (CAS
RN 105565-56-8); flibanserin (CAS RN 167933-07-5); repinotan (CAS
RN 144980-29-0); lesopitron (CAS RN 132449-46-8); piclozotan (CAS
RN 182415-09-4); Aripiprazole, Org-13011
(144-trifluoromethyl-2-pyridinyl)-4-[4-[2-oxo-l-pyrrolidinyl]butyl]pipera-
zine (E)-2-butenedioate); SDZ-MAR-327 (see Christian et al.
"Positron emission tomographic analysis of central dopamine D1
receptor binding in normal subjects treated with the atypical
neuroleptic, SDZ MAR 327." Int J Mol Med. 1998 1(1):243-7); MKC-242
((S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole
HCl); vilazodone; sarizotan (CAS RN 177975-08-5); roxindole (CAS RN
112192-04-8) or roxindole methanesulfonate (CAS RN 119742-13-1);
alnespirone (CAS RN 138298-79-0); bromerguride (CAS RN 83455-48-5);
xaliproden (CAS RN 135354-02-8); mazapertine succinate (CAS RN
134208-18-7) or mazapertine (CAS RN 134208-17-6); PRX-00023;
F-13640
((3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-a-
mino]methyl]piperidin-1-yl]methanone, fumaric acid salt);
eptapirone (CAS RN 179756-85-5); Ziprasidone (CAS RN 146939-27-7);
Sunepitron (see Becker et al. "G protein-coupled receptors: In
silico drug discovery in 3D" PNAS 2004 101(31):11304-11309);
umespirone (CAS RN 107736-98-1); SLV-308; bifeprunox; flesinoxan
(CAS RN 98206-10-1); and zalospirone (CAS RN 114298-18-9).
[0216] Yet further non-limiting examples include AP-521 (partial
agonist from AsahiKasei) and Du-123015 (from Solvay).
[0217] Alternatively, the agent used with a muscarinic agent, such
as an inhibitor of AChE activity, may be a reported 5HT4 receptor
agonist (or partial agonist). In some embodiments, a reported 5HT4
receptor agonist or partial agonist is a substituted benzamide,
such as cisapride; individual, or a combination of, cisapride
enantiomers ((+) cisapride and (-) cisapride); mosapride; and
renzapride as non-limiting examples. In other embodiments, the
chemical entity is a benzofuran derivative, such as prucalopride.
Additional embodiments include indoles, such as tegaserod, or
benzimidazolones. Other non-limiting chemical entities reported as
a 5HT4 receptor agonist or partial agonist include zacopride (CAS
RN 90182-92-6), SC-53116 (CAS RN 141196-99-8) and its racemate
SC-49518 (CAS RN 146388-57-0), BIMU1 (CAS RN 127595-43-1), TS-951
(CAS RN 174486-39-6), or ML10302 CAS RN 148868-55-7). Additional
non-limiting chemical entities include metoclopramide,
5-methoxytryptamine, RS67506,
2-[1-(4-piperonyl)piperazinyl]benzothiazole, RS66331, BIMU8, SB
205149 (the n-butyl quaternary analog of renzapride), or an indole
carbazimidamide as described by Buchheit et al. ("The serotonin
5-HT4 receptor. 2. Structure-activity studies of the indole
carbazimidamide class of agonists." J Med Chem. (1995)
38(13):2331-8). Yet additional non-limiting examples include
norcisapride (CAS RN 102671-04-5) which is the metabolite of
cisapride; mosapride citrate; the maleate form of tegaserod (CAS RN
189188-57-6); zacopride hydrochloride (CAS RN 99617-34-2);
mezacopride (CAS RN 89613-77-4); SK-951
((.+-.)-4-amino-N-(2-(1-azabicyclo(3.3.0)octan-5-yl)ethyl)-5-chloro-2,3-d-
ihydro-2-methylbenzo(b)furan-7-carboxamide hemifumarate); ATI-7505,
a cisapride analog from ARYx Therapeutics; SDZ-216-454, a selective
5HT4 receptor agonist that stimulates cAMP formation in a
concentration dependent manner (see Markstein et al.
"Pharmacological characterisation of 5-HT receptors positively
coupled to adenylyl cyclase in the rat hippocampus." Naunyn
Schmiedebergs Arch Pharmacol. (1999) 359(6):454-9); SC-54750, or
Aminomethylazaadamantane; Y-36912, or
4-amino-N-[1-[3-(benzylsulfonyl)propyl]piperidin-4-ylmethyl]-5-chloro-2-m-
ethoxybenzamide as disclosed by Sonda et al. ("Synthesis and
pharmacological properties of benzamide derivatives as selective
serotonin 4 receptor agonists." Bioorg Med Chem. (2004)
12(10):2737-47); TKS159, or
4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidi-
nyl]benzamide, as reported by Haga et al. ("Effect of TKS159, a
novel 5-hydroxytryptamine4 agonist, on gastric contractile activity
in conscious dogs."; RS67333, or
1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidiny1)-1-propan-
one; KDR-5169, or
4-amino-5-chloro-N-[1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl]-2-(2-hydr-
o xyethoxy)benzamide hydrochloride dihydrate as reported by Tazawa,
et al. (2002) "KDR-5169, a new gastrointestinal prokinetic agent,
enhances gastric contractile and emptying activities in dogs and
rats." Eur J Pharmacol 434(3):169-76); SL65.0155, or
5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenyl
ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride;
and Y-34959, or
4-Amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)penty-
l]piperidin-4-ylmethyl]benzamide.
[0218] Other non-limiting reported 5HT4 receptor agonists and
partial agonists for use in combination with a muscarinic agent,
such as an inhibitor of AChE activity, include metoclopramide (CAS
RN 364-62-5), 5-methoxytryptamine (CAS RN 608-07-1), RS67506 (CAS
RN 168986-61-6), 2-[1-(4-piperonyl)piperazinyl]benzothiazole (CAS
RN 155106-73-3), RS66331 (see Buccafusco et al. "Multiple Central
Nervous System Targets for Eliciting Beneficial Effects on Memory
and Cognition." (2000) Pharmacology 295(2):438-446), BIMU8
(endo-N-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dehydro-2-oxo-3-(prop-2-
-yl)-1H-benzimid-azole-1-carboxamide), or SB 205149 (the n-butyl
quaternary analog of renzapride). Compounds related to
metoclopramide, such as metoclopramide dihydrochloride (CAS RN
2576-84-3) or metoclopramide dihydrochloride (CAS RN 5581-45-3) or
metoclopramide hydrochloride (CAS RN 7232-21-5 or 54143-57-6) may
also be used in a combination or method as described herein.
[0219] Additionally, the agent used with a muscarinic agent, such
as an inhibitor of AChE activity, may be a reported 5HT3 receptor
antagonist such as azasetron (CAS RN 123039-99-6); Ondansetron (CAS
RN 99614-02-5) or Ondansetron hydrochloride (CAS RN 99614-01-4);
Cilansetron (CAS RN 120635-74-7); Aloxi or Palonosetron
Hydrochloride (CAS RN 135729-62-3); Palenosetron (CAS RN
135729-61-2 or 135729-56-5); Cisplatin (CAS RN 15663-27-1);
Lotronex or Alosetron hydrochloride (CAS RN 122852-69-1); Anzemet
or Dolasetron mesylate (CAS RN 115956-13-3); zacopride or
R-Zacopride; E-3620
([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[-
(1-methyl-2-butynyl)oxy]benzamide) or E-3620 HCl
(3(S)-endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-(1-
-methyl-2-butinyl)oxy)-benzamide-HCl); YM 060 or Ramosetron
hydrochloride (CAS RN 132907-72-3); a thieno[2,3-d]pyrimidine
derivative antagonist described in U.S. Pat. No. 6,846,823, such as
DDP 225 or MCI 225 (CAS RN 135991-48-9); Marinol or Dronabinol (CAS
RN 1972-08-3); or Lac Hydrin or Ammonium lactate (CAS RN 515-98-0);
Kytril or Granisetron hydrochloride (CAS RN 107007-99-8);
Bemesetron (CAS RN 40796-97-2); Tropisetron (CAS RN 89565-68-4);
Zatosetron (CAS RN 123482-22-4); Mirisetron (CAS RN 135905-89-4) or
Mirisetron maleate (CAS RN 148611-75-0); or renzapride (CAS RN
112727-80-7).
[0220] Additionally, the agent used with a muscarinic agent, such
as an inhibitor of AChE activity, may be a reported 5HT2A/2C
receptor antagonist such as Ketanserin (CAS RN 74050-98-9) or
ketanserin tartrate; risperidone; olanzapine; adatanserin (CAS RN
127266-56-2); Ritanserin (CAS RN 87051-43-2); Deramciclane (CAS RN
120444-71-5); Geoden or Ziprasidone hydrochloride (CAS RN
138982-67-9); Zeldox or Ziprasidone or Ziprasidone hydrochloride;
EMD 281014
(7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl]-1H-indole-3-carb-
onitrile HC1); MDL 100907 or M100907 (CAS RN 139290-65-6); Effexor
XR (Venlafaxine formulation); Zomaril or Iloperidone; quetiapine
(CAS RN 111974-69-7) or Quetiapine fumarate (CAS RN 111974-72-2) or
Seroquel; SB 228357 or SB 243213 (see Bromidge et al.
"Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor
inverse agonists: identification of
5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoro-
methylindoline (SB-243213) as a potential antidepressant/anxiolytic
agent." J Med Chem. 2000 43(6):1123-34; SB 220453 or Tonabersat
(CAS RN 175013-84-0); Sertindole (CAS RN 106516-24-9); Eplivanserin
(CAS RN 130579-75-8) or Eplivanserin fumarate (CAS RN 130580-02-8);
Lubazodone hydrochloride (CAS RN 161178-10-5); Cyproheptadine (CAS
RN 129-03-3); Pizotyline or pizotifen (CAS RN 15574-96-6);
Mesulergine (CAS RN 64795-35-3); Irindalone (CAS RN 96478-43-2);
MDL 11939 (CAS RN 107703-78-6); or pruvanserin (CAS RN
443144-26-1).
[0221] Additional non-limiting examples of modulators include
reported 5-HT2A receptor inverse agonists, such as ACP 103 (CAS RN:
868855-07-6), APD125 (from Arena Pharmaceuticals), AVE 8488 (from
Sanofi-Aventis) or TGWOOAD/AA(from Fabre Kramer
Pharmaceuticals).
[0222] Additionally, the agent used with a muscarinic agent, such
as an inhibitor of AChE activity, may be a reported 5HT6 receptor
antagonist such as SB-357134
(N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonam-
ide); SB-271046
(5-chloro-N-(4-methoxy-3-(piperazin-1-yl)phenyl)-3-methylbenzo[b]thiophen-
e-2-sulfonamide); Ro 04-06790
(N-(2,6-bis(methylamino)pyrimidin-4-yl)-4-aminobenzenesulfonamide);
Ro 63-0563 (4-amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene
sulfonamide); clozapine or its metabolite N-desmethylclozapine;
olanzapine (CAS RN 132539-06-1); fluperlapine (CAS RN 67121-76-0);
seroquel (quetiapine or quetiapine fumarate); clomipramine (CAS RN
303-49-1); amitriptyline (CAS RN50-48-6); doxepin (CAS RN
1668-19-5); nortryptyline (CAS RN 72-69-5); 5-methoxytryptamine
(CAS RN 608-07-1); bromocryptine (CAS RN 25614-03-3); octoclothepin
(CAS RN 13448-22-1); chlorpromazine (CAS RN 50-53-3); loxapine (CAS
RN 1977-10-2); fluphenazine (CAS RN 69-23-8); or GSK 742457
(presented by David Witty, "Early Optimisation of in vivo Activity:
the discovery of 5-HT6 Receptor Antagonist 742457" GlaxoSmithKline
at SCIpharm 2006, International. Pharmaceutical Industry Conference
in Edinburgh, 16 May 2006).
[0223] As an additional non-limiting example, the reported 5HT6
modulator may be SB-258585
(4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzen
esulphonamide); PRX 07034 (from Predix Pharmaceuticals) or a
partial agonist, such as E-6801
(6-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)imidazo[2,1-b]thiaz-
ole-5-sulfonamide) or E-6837
(5-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)naphthalene-2-sulfo-
namide).
[0224] Additionally, the agent used with a muscarinic agent, such
as an inhibitor of AChE activity, may be a reported trace amine
(TA), or a metabolite, precursor, prodrug, or analogue thereof,
receptor modulator. TAs are endogenous, CNS-active amines that are
structurally related to classical biogenic amines (e.g., dopamine,
5-HT, norepinephrine). The methods of the disclosure thus include
administration of one or more reported TAs in a combination.
[0225] Certain food products, e.g., chocolates, cheeses, and wines,
can also provide a significant dietary source of TAs and/or
TA-related compounds. Non-limiting examples of mammalian TAs useful
as constitutive factors include, but are not limited to,
tryptamine, .rho.-tyramine, m-tyramine, octopamine, synephrine and
.beta.-phenylethylamine (.beta.-PEA). Additional useful TA-related
compounds include, but are not limited to, 5-hydroxytryptamine,
amphetamine, bufotenin, 5-methoxytryptamine,
dihydromethoxytryptamine, and phenylephrine.
[0226] In some embodiments, the constitutive factor is a biogenic
amine or a ligand of a trace amine-associated receptor (TAAR),
and/or an agent that mediates one or more biological effects of a
TA. TAs have been shown to bind to and activate a number of unique
receptors, termed TAARs, which comprise a family of G-protein
coupled receptors (TAAR1-TAAR9) with homology to classical biogenic
amine receptors. For example, TAAR1 is activated by both tyramine
and .beta.-PEA.
[0227] Thus non-limiting embodiments include methods and
combination compositions wherein the constitutive factor is
.beta.-PEA, which has been indicated as having a significant
neuromodulatory role in the mammalian CNS and is found at
relatively high levels in the hippocampus (e.g., Taga et al.,
Biomed Chromatogr., 3(3): 118-20 (1989)); a metabolite, prodrug,
precursor, or other analogue of .beta.-PEA, such as the .beta.-PEA
precursor L-phenylalanine, the .beta.-PEA metabolite
.beta.-phenylacetic acid (.beta.-PAA), or the .beta.-PEA analogues
methylphenidate, amphetamine, and related compounds.
[0228] Most TAs have a short half-life (e.g., less than about 30 s)
due, e.g., to their rapid extracellular metabolism by MAO-A and/or
MAO-B, which provide the major pathway for TA metabolism. Thus, in
some embodiments, TA levels are regulated by modulating the
activity of MAO-A and/or MAO-B. For example, in some embodiments,
endogenous TA levels are increased (and TA signaling is enhanced)
by administering an inhibitor of MAO-A and/or MAO-B, in combination
with a muscarinic agent, such as an inhibitor of AChE activity, as
described herein. Non-limiting examples of inhibitors of monoamine
oxidase (MAO) include reported inhibitors of the MAO-A isoform,
which preferentially deaminates 5-hydroxytryptamine (serotonin)
(5-HT) and norepinephrine (NE), and/or the MAO-B isoform, which
preferentially deaminates phenylethylamine (PEA) and benzylamine
(both MAO-A and MAO-B metabolize Dopamine (DA)). In various
embodiments, MAO inhibitors may be irreversible or reversible
(e.g., reversible inhibitors of MAO-A (RIMA)), and may have varying
potencies against MAO-A and/or MAO-B (e.g., non-selective dual
inhibitors or isoform-selective inhibitors). Non-limiting examples
of MAO inhibitors useful in methods described herein include
clorgyline, L-deprenyl, isocarboxazid (Marplan), ayahuasca,
nialamide, iproniazide, iproclozide, moclobemide (Aurorix),
phenelzine (Nardil), tranylcypromine (Parnate) (the congeneric of
phenelzine), toloxatone, levo-deprenyl (Selegiline), harmala, RIMAs
(e.g., moclobemide, described in Da Prada et al., J Pharmacol Exp
Ther 248: 400-414 (1989); brofaromine; and befloxatone, described
in Curet et al., J Affect Disord 51: 287-303 (1998)), lazabemide
(Ro 19 6327), described in Ann. Neurol., 40(1): 99-107 (1996), and
SL25.1131, described in Aubin et al., J. Pharmacol. Exp. Ther.,
310: 1171-1182 (2004).
[0229] In embodiments relating to a biogenic amine modulator used
in a combination or method with a muscarinic agent as disclosed
herein, the modulator may be (i) a norepinephrine and dopamine
reuptake inhibitor, such as bupropion (described, e.g., in U.S.
Pat. Nos. 3,819,706 and 3,885,046), or (S,S)-hydroxybupropion
(described, e.g., in U.S. Pat. No. 6,342,496); (ii) selective
dopamine reuptake inhibitors, such as medifoxamine, amineptine
(described, e.g., in U.S. Pat. Nos. 3,758,528 and 3,821,249),
GBR12909, GBR12783 and GBR13069, described in Andersen, Eur J
Pharmacol, 166:493-504 (1989); or (iii) a biogenic amine "releaser"
which stimulates the release of biogenic amines, such as
fenfluramine or p-chloroamphetamine (PCA), or the dopamine,
norepinephrine, and serotonin releasing compound amineptine
(described, e.g., in U.S. Pat. Nos. 3,758,528 and 3,821,249).
[0230] The agent used with a muscarinic agent, such as an inhibitor
of AChE activity, may be a reported phosphodiesterase (PDE)
inhibitor. In some embodiments, a reported inhibitor of PDE
activity include an inhibitor of a cAMP-specific PDE. Non-limiting
examples of cAMP specific PDE inhibitors useful in the methods
described herein include a pyrrolidinone, such as a compound
disclosed in U.S. Pat. No. 5,665,754, US20040152754 or
US20040023945; a quinazolineone, such as a compound disclosed in
U.S. Pat. Nos. 6,747,035 or 6,828,315, WO 97/49702 or WO 97/42174;
a xanthine derivative; a phenylpyridine, such as a compound
disclosed in U.S. Pat. Nos. 6,410,547 or 6,090,817, or WO 97/22585;
a diazepine derivative, such as a compound disclosed in WO
97/36905; an oxime derivative, such as a compound disclosed in U.S.
Pat. No. 5,693,659 or WO 96/00215; a naphthyridine, such as a
compound described in U.S. Pat. Nos. 5,817,670, 6,740,662,
6,136,821, 6,331,548, 6,297,248, 6,541,480, 6,642,250, or
6,900,205, or Trifilieff et al., Pharmacology, 301(1): 241-248
(2002), or Hersperger et al., J Med Chem., 43(4):675-82 (2000); a
benzofuran, such as a compound disclosed in U.S. Pat. Nos.
5,902,824, 6,211,203, 6,514,996, 6,716,987, 6,376,535, 6,080,782,
or 6,054,475, or EP 819688, EP685479, or Perrier et al., Bioorg.
Med. Chem. Lett. 9:323-326 (1999); a phenanthridine, such as that
disclosed in U.S. Pat. Nos. 6,191,138, 6,121,279, or 6,127,378; a
benzoxazole, such as that disclosed in U.S. Pat. Nos. 6,166,041 or
6,376,485; a purine derivative, such as a compound disclosed in
U.S. Pat. No. 6,228,859; a benzamide, such as a compound described
in U.S. Pat. Nos. 5,981,527 or 5,712,298, or WO95/01338, WO
97/48697 or Ashton et al., J. Med Chem 37: 1696-1703 (1994); a
substituted phenyl compound, such as a compound disclosed in U.S.
Pat. Nos. 6,297,264, 5,866,593,6,5 58,590 3,46,245,774, 6,197,792,
6,080,790, 6,077,854, 5,962,483, 5,674,880, 5,786,354, 5,739,144,
5,776,958, 5,798,373, 5,891,896, 5,849,770, 5,550,137, 5,340,827,
5,780,478, 5,780,477, or 5,633,257, or WO 95/35283; a substituted
biphenyl compound, such as that disclosed in U.S. Pat. No.
5,877,190; or a quinilinone, such as a compound described in U.S.
Pat. No. 6,800,625 or WO 98/14432.
[0231] Additional non-limiting examples of reported cAMP-specific
PDE inhibitors useful in methods disclosed herein include a
compound disclosed in U.S. Pat. Nos. 6,818,651, 6,737,436,
6,613,778, 6,617,357, 6,146,876, 6,838,559, 6,884,800, 6,716,987,
6,514,996, 6,376,535, 6,740,655, 6,559,168, 6,069,151, 6,365,585,
6,313,116, 6,245,774, 6,011,037, 6,127,363, 6,303,789, 6,316,472,
6,348,602, 6,331,543, 6,333,354, 5,491,147, 5,608,070, 5,622,977,
5,580,888, 6,680,336, 6,569,890, 6,569,885, 6,500,856, 6,486,186,
6,458,787, 6,455,562, 6,444,671, 6,423,710, 6,376,489, 6,372,777,
6,362,213, 6,313,156, 6,294,561, 6,258,843, 6,258,833, 6,121,279,
6,043,263, RE38,624, 6,297,257, 6,251,923, 6,613,794, 6,407,108,
6,107,295, 6,103,718, 6,479,494, 6,602,890, 6,545,158, 6,545,025,
6,498,160, 6,743,802, 6,787,554, 6,828,333, 6,869,945, 6,894,041,
6,924,292, 6,949,573, 6,953,810, 6,156,753, 5,972,927, 5,962,492,
5,814,651, 5,723,460, 5,716,967, 5,686,434, 5,502,072, 5,116,837,
5,091,431; 4,670,434; 4,490,371; 5,710,160, 5,710,170, 6,384,236,
or 3,941,785, or US20050119225, US20050026913, US20050059686,
US20040138279, US20050222138, US20040214843, US20040106631, US
20030045557, US 20020198198, US20030162802, US20030092908, US
20030104974, US20030100571, 20030092721, US20050148604, WO
99/65880, WO 00/26201, WO 98/06704, WO 00/59890, WO 9907704, WO
9422852, WO 98/20007, WO 02/096423, WO 98/18796, WO 98/02440, WO
02/096463, WO 97/44337, WO 97/44036, WO 97/44322, EP 0763534, Aoki
et al., J Pharmacol Exp Ther., 295(1):255-60 (2000), Del Piaz et
al., Eur. J. Med. Chem., 35; 463-480 (2000), or Barnette et al.,
Pharmacol. Rev. Commun. 8: 65-73 (1997).
[0232] In some embodiments, the reported cAMP-specific PDE
inhibitor is Cilomilast (SB-207499); Filaminast; Tibenelast
(LY-186655); Ibudilast; Piclamilast (RP 73401); Doxofylline;
Cipamfylline (HEP-688); atizoram (CP-80633); theophylline;
isobutylmethylxanthine; Mesopram (ZK-117137); Zardaverine;
vinpocetine; Rolipram (ZK-62711); Arofylline (LAS-31025);
roflumilast (BY-217); Pumafentrin (BY-343); Denbufylline; EHNA;
milrinone; Siguazodan; Zaprinast; Tolafentrine; Isbufylline; IBMX;
1C-485; dyphylline; verolylline; bamifylline; pentoxyfilline;
enprofilline; lirimilast (BAY 19-8004); filaminast (WAY-PDA-641);
benafentrine; trequinsin; nitroquazone; cilostamide; vesnarinone;
piroximone; enoximone; amrinone; olprinone; imazodan or
5-methyl-imazodan; indolidan; anagrelide; carbazeran; ampizone;
emoradan; motapizone; phthalazinol; lixazinone (RS 82856);
quazinone; bemorandan (RWJ 22867); adibendan (BM 14,478);
Pimobendan (MCI-154); Saterinone (BDF 8634); Tetomilast (OPC-6535);
benzafentrine; sulmazole (ARL 115); Revizinone; 349-U-85;
AH-21-132; ATZ-1993; AWD-12-343; AWD-12-281; AWD-12-232; BRL 50481;
CC-7085; CDC-801; CDC-998; CDP-840; CH-422; CH-673; CH-928;
CH-3697; CH-3442; CH-2874; CH-4139; Chiroscience 245412; CI-930;
CI-1018; CI-1044; CI-1118; CP-353164; CP-77059; CP-146523;
CP-293321; CP-220629; CT-2450; CT-2820; CT-3883; CT-5210; D-4418;
D-22888; E-4021; EMD 54622; EMD-53998; EMD-57033; GF-248; GW-3600;
IC-485; ICI 63197; ICI 153,110; IPL-4088; KF-19514; KW-4490;
L-787258; L-826141; L-791943; LY181512; NCS-613; NM-702; NSP-153;
NSP-306; NSP-307; Org-30029; Org-20241; Org-9731; ORG 9935;
PD-168787; PD-190749; PD-190036; PDB-093; PLX650; PLX369; PLX371;
PLX788; PLX939; Ro-20-1724; RPR-132294; RPR-117658A; RPR-114597;
RPR-122818; RPR-132703; RS-17597; RS-25344; RS-14203; SCA 40;
Sch-351591; SDZ-ISQ-844; SDZ-MKS-492; SKF 94120; SKF-95654;
SKF-107806; SKF 96231; T-440; T-2585; WAY-126120; WAY-122331;
WAY-127093B; WIN-63291; WIN-62582; V-11294A; VMX 554; VMX 565;
XT-044; XT-611; Y-590; YM-58897; YM-976; ZK-62711; methyl
3-[6-(2H-3,4,5,6-tetrahydropyran-2-yloxy)-2-(3-thienylcarbonyl)benzo[b]fu-
ran-3-yl]propanoate;
4-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-2-methylbenzoic acid;
methyl
3-{2-[(4-chlorophenyl)carbonyl]-6-hydroxybenzo[b]furan-3-yl}propanoate;
(R* ,R*)-(.+-.)-methyl
3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-1-pyrrolidinecar-
boxylat; or
4-(3-bromophenyl)-1-ethyl-7-methylhydropyridino[2,3-b]pyridin-2-one.
[0233] In some embodiments, the reported PDE inhibitor inhibits a
cGMP-specific PDE. Non-limiting examples of a cGMP specific PDE
inhibitor for use in the combinations and methods described herein
include a pyrimidine or pyrimidinone derivative, such as a compound
described in U.S. Pat. Nos. 6,677,335, 6,458,951, 6,251,904,
6,787,548, 5,294,612, 5,250,534, or 6,469,012, WO 94/28902, WO
96/16657, EP0702555, and Eddahibi, Br. J. Pharmacol., 125(4):
681-688 (1988); a griseolic acid derivative, such as a compound
disclosed in U.S. Pat. No. 4,460,765; a 1-arylnaphthalene lignan,
such as that described in Ukita, J. Med. Chem. 42(7): 1293-1305
(1999); a quinazoline derivative, such as
4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline) or a
compound described in U.S. Pat. Nos. 3,932,407 or 4,146,718, or
RE31,617; a pyrroloquinolone or pyrrolopyridinone, such as that
described in U.S. Pat. Nos. 6,686,349, 6,635,638, 6,818,646,
US20050113402; a carboline derivative, such a compound described in
U.S. Pat. Nos. 6,492,358, 6,462,047, 6,821,975, 6,306,870,
6,117,881, 6,043,252, or 3,819,631, US20030166641, WO 97/43287,
Daugan et al., J Med Chem., 46(21):4533-42 (2003), or Daugan et
al., J Med Chem., 9;46(21):4525-32 (2003); an imidazo derivative,
such as a compound disclosed in U.S. Pat. Nos. 6,130,333,
6,566,360, 6,362,178, or 6,582,351, US20050070541, or
US20040067945; or a compound described in U.S. Pat. Nos. 6,825,197,
5,719,283, 6,943,166, 5,981,527, 6,576,644, 5,859,009, 6,943,253,
6,864,253, 5,869,516, 5,488,055, 6,140,329, 5,859,006, or
6,143,777, WO 96/16644, WO 01/19802, WO 96/26940, Dunn, Org. Proc.
Res. Dev., 9: 88-97 (2005), or Bi et al., Bioorg Med Chem Left.,
11(18):2461-4 (2001).
[0234] In some embodiments, the PDE inhibitor used in a combination
or method disclosed herein is caffeine. In some embodiments, the
caffeine is administered in a formulation comprising a muscarinic
agent, such as an inhibitor of AChE activity. In other embodiments,
the caffeine is administered simultaneously with the muscarinic
agent. In alternative embodiments, the caffeine is administered in
a formulation, dosage, or concentration lower or higher than that
of a caffeinated beverage such as coffee, tea, or soft drinks. In
further embodiments, the caffeine is administered by a non-oral
means, including, but not limited to, parenteral (e.g.,
intravenous, intradermal, subcutaneous, inhalation), transdermal
(topical), transmucosal, rectal, or intranasal (including, but not
limited to, inhalation of aerosol suspensions for delivery of
compositions to the nasal mucosa, trachea and bronchioli)
administration. The disclosure includes embodiments with the
explicit exclusion of caffeine or another one or more of the
described agents for use in combination with a muscarinic
agent.
[0235] In further alternative embodiments, the caffeine is in an
isolated form, such as that which is separated from one or more
molecules or macromolecules normally found with caffeine before use
in a combination or method as disclosed herein. In other
embodiments, the caffeine is completely or partially purified from
one or more molecules or macromolecules normally found with the
caffeine. Exemplary cases of molecules or macromolecules found with
caffeine include a plant or plant part, an animal or animal part,
and a food or beverage product.
[0236] Non-limiting examples of a reported PDE1 inhibitor include
IBMX; vinpocetine; MMPX; KS-505a; SCH-51866; W-7; PLX650; PLX371;
PLX788; a phenothiazines; or a compound described in U.S. Pat. No.
4,861,891.
[0237] Non-limiting examples of a PDE2 inhibitor include EHNA;
PLX650; PLX369; PLX788; PLX 939; Bay 60-7550 or a related compound
described in Boess et al., Neuropharmacology, 47(7):1081-92 (2004);
or a compound described in US20020132754.
[0238] Non-limiting examples of reported PDE3 inhibitors include a
dihydroquinolinone compound such as cilostamide, cilostazol,
vesnarinone, or OPC 3911; an imidazolone such as piroximone or
enoximone; a bipyridine such as milrinone, amrinone or olprinone;
an imidazoline such as imazodan or 5-methyl-imazodan; a
pyridazinone such as indolidan; LY181512 (see Komas et al.
"Differential sensitivity to cardiotonic drugs of cyclic AMP
phosphodiesterases isolated from canine ventricular and
sinoatrial-enriched tissues." J Cardiovasc Pharmacol. 1989
14(2):213-20); ibudilast; isomazole; motapizone; phthalazinol;
trequinsin; lixazinone (RS 82856); Y-590; SKF 94120; quazinone; ICI
153,110; bemorandan (RWJ 22867); siguazodan (SK&F 94836);
adibendan (BM 14,478); Pimobendan (UD-CG 115, MCI-154); Saterinone
(BDF 8634); NSP-153; zardaverine; a quinazoline; benzafentrine;
sulmazole (ARL 115); ORG 9935; CI-930; SKF-95654; SDZ-MKS-492;
349-U-85; EMD-53998; EMD-57033; NSP-306; NSP-307; Revizinone;
NM-702; WIN-62582; ATZ-1993; WIN-63291; ZK-62711; PLX650; PLX369;
PLX788; PLX939; anagrelide; carbazeran; ampizone; emoradan; or a
compound disclosed in U.S. Pat. No. 6,156,753.
[0239] Non-limiting examples of reported PDE4 inhibitors include a
pyrrolidinone, such as a compound disclosed in U.S. Pat. No.
5,665,754, US20040152754 or US20040023945; a quinazolineone, such
as a compound disclosed in U.S. Pat. Nos. 6,747,035 or 6,828,315,
WO 97/49702 or WO 97/42174; a xanthine derivative; a
phenylpyridine, such as a compound disclosed in U.S. Pat. Nos.
6,410,547 or 6,090,817 or WO 97/22585; a diazepine derivative, such
as a compound disclosed in WO 97/36905; an oxime derivative, such
as a compound disclosed in U.S. Pat. No. 5,693,659 or WO 96/00215;
a naphthyridine, such as a compound described in U.S. Pat. Nos.
5,817,670, 6,740,662, 6,136,821, 6,331,548, 6,297,248, 6,541,480,
6,642,250, or 6,900,205, Trifilieff et al., Pharmacology, 301(1):
241-248 (2002) or Hersperger et al., J Med Chem., 43(4):675-82
(2000); a benzofuran, such as a compound disclosed in U.S. Pat.
Nos. 5,902,824, 6,211,203, 6,514,996, 6,716,987, 6,376,535,
6,080,782, or 6,054,475, EP 819688, EP685479, or Perrier et al.,
Bioorg. Med. Chem. Lett. 9:323-326 (1999); a phenanthridine, such
as that disclosed in U.S. Pat. Nos. 6,191,138, 6,121,279, or
6,127,378; a benzoxazole, such as that disclosed in U.S. Pat. Nos.
6,166,041 or 6,376,485; a purine derivative, such as a compound
disclosed in U.S. Pat. No. 6,228,859; a benzamide, such as a
compound described in U.S. Pat. Nos. 5,981,527 or 5,712,298, WO
95/01338, WO 97/48697, or Ashton et al., J. Med Chem 37: 1696-1703
(1994); a substituted phenyl compound, such as a compound disclosed
in U.S. Pat. Nos. 6,297,264, 5,866,593,65 5,859,034, 6,245,774,
6,197,792, 6,080,790, 6,077,854, 5,962,483, 5,674,880, 5,786,354,
5,739,144, 5,776,958, 5,798,373, 5,891,896, 5,849,770, 5,550,137,
5,340,827, 5,780,478, 5,780,477, or 5,633,257, or WO 95/35283; a
substituted biphenyl compound, such as that disclosed in U.S. Pat.
No. 5,877,190; or a quinilinone, such as a compound described in
U.S. Pat. No. 6,800,625 or WO 98/14432.
[0240] Additional examples of reported PDE4 inhibitors useful in
methods provided herein include a compound disclosed in U.S. Pat.
Nos. 6,716,987, 6,514,996, 6,376,535, 6,740,655, 6,559,168,
6,069,151, 6,365,585, 6,313,116, 6,245,774, 6,011,037, 6,127,363,
6,303,789, 6,316,472, 6,348,602, 6,331,543, 6,333,354, 5,491,147,
5,608,070, 5,622,977, 5,580,888, 6,680,336, 6,569,890, 6,569,885,
6,500,856, 6,486,186, 6,458,787, 6,455,562, 6,444,671, 6,423,710,
6,376,489, 6,372,777, 6,362,213, 6,313,156, 6,294,561, 6,258,843,
6,258,833, 6,121,279, 6,043,263, RE38,624, 6,297,257, 6,251,923,
6,613,794, 6,407,108, 6,107,295, 6,103,718, 6,479,494, 6,602,890,
6,545,158, 6,545,025, 6,498,160, 6,743,802, 6,787,554, 6,828,333,
6,869,945, 6,894,041, 6,924,292, 6,949,573, 6,953,810, 5,972,927,
5,962,492, 5,814,651, 5,723,460, 5,716,967, 5,686,434, 5,502,072,
5,116,837, 5,091,431; 4,670,434; 4,490,371; 5,710,160, 5,710,170,
6,384,236, or 3,941,785, US20050119225, US20050026913, WO 99/65880,
WO 00/26201, WO 98/06704, WO 00/59890, W09907704, W09422852, WO
98/20007, WO 02/096423, WO 98/18796, WO 98/02440, WO 02/096463, WO
97/44337, WO 97/44036, WO 97/44322, EP 0763534, Aoki et al., J
Pharmacol Exp Ther., 295(1):255-60 (2000), Del Piaz et al., Eur. J.
Med. Chem., 35; 463-480 (2000), or Barnette et al., Pharmacol. Rev.
Commun. 8: 65-73 (1997).
[0241] In some embodiments, the reported PDE4 inhibitor is
Cilomilast (SB-207499); Filaminast; Tibenelast (LY-186655);
Ibudilast; Piclamilast (RP 73401); Doxofylline; Cipamfylline
(HEP-688); atizoram (CP-80633); theophylline;
isobutylmethylxanthine; Mesopram (ZK-117137); Zardaverine;
vinpocetine; Rolipram (ZK-62711); Arofylline (LAS-31025);
roflumilast (BY-217); Pumafentrin (BY-343); Denbufylline; EHNA;
milrinone; Siguazodan; Zaprinast; Tolafentrine; Isbufylline; IBMX;
1C-485; dyphylline; verolylline; bamifylline; pentoxyfilline;
enprofilline; lirimilast (BAY 19-8004); filaminast (WAY-PDA-641);
benafentrine; trequinsin; nitroquazone; Tetomilast (OPC-6535);
AH-21-132; AWD-12-343; AWD-12-281; AWD-12-232; CC-7085; CDC-801;
CDC-998; CDP-840; CH-422; CH-673; CH-928; CH-3697; CH-3442;
CH-2874; CH-4139; Chiroscience 245412; CI-1018; CI-1044; CI-1118;
CP-353164; CP-77059; CP-146523; CP-293321; CP-220629; CT-2450;
CT-2820; CT-3883; CT-5210; D-4418; D-22888; E-4021; EMD 54622;
GF-248; GW-3600; IC-485; ICI 63197; IPL-4088; KF-19514; KW-4490;
L-787258; L-826141; L-791943; NCS-613; Org-30029; Org-20241;
Org-9731; PD-168787; PD-190749; PD-190036; PDB-093; PLX650; PLX369;
PLX371; PLX788; PLX939; Ro-20-1724; RPR-132294; RPR-117658A;
RPR-114597; RPR-122818; RPR-132703; RS-17597; RS-25344; RS-14203;
SCA 40; Sch-351591; SDZ-ISQ-844; SKF-107806; SKF 96231; T-440;
T-2585; WAY-126120; WAY-122331; WAY-127093B; V-11294A;VMX 554; VMX
565; XT-044; XT-611; YM-58897; YM-976; methyl
3-[6-(2H-3,4,5,6-tetrahydropyran-2-yloxy)-2-(3-thienylcarbonyl)benzo[b]fu-
ran-3-yl]propanoate;
4-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-2-methylbenzoic acid;
methyl
3-{2-[(4-chlorophenyl)carbonyl]-6-hydroxybenzo[b]furan-3-yl}propanoate;
(R*,R*)-(.+-.)-methyl
3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-1-pyrrolidinecar-
boxylat; or
4-(3-bromophenyl)-1-ethyl-7-methylhydropyridino[2,3-b]pyridin-2-one.
[0242] Non-limiting examples of a reported PDE5 inhibitor useful in
a combination or method described herein include a pyrimidine or
pyrimidinone derivative, such as a compound described in U.S. Pat.
Nos. 6,677,335, 6,458,951, 6,251,904, 6,787,548, 5,294,612,
5,250,534, or 6,469,012, WO 94/28902, WO 96/16657, EP0702555, or
Eddahibi, Br. J. Pharmacol., 125(4): 681-688 (1988); a griseolic
acid derivative, such as a compound disclosed in U.S. Pat. No.
4,460,765; a 1-arylnaphthalene lignan, such as that described in
Ukita, J. Med. Chem. 42(7): 1293-1305 (1999); a quinazoline
derivative, such as
4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline) or a
compound described in U.S. Pat. Nos. 3,932,407 or 4,146,718, or
RE31,617; a pyrroloquinolones or pyrrolopyridinone, such as that
described in U.S. Pat. Nos. 6,686,349, 6,635,638, or 6,818,646,
US20050113402; a carboline derivative, such a compound described in
U.S. Pat. Nos. 6,492,358, 6,462,047, 6,821,975, 6,306,870,
6,117,881, 6,043,252, or 3,819,631, US20030166641, WO 97/43287,
Daugan et al., J Med Chem., 46(21):4533-42 (2003), and Daugan et
al., J Med Chem., 9;46(21):4525-32 (2003); an imidazo derivative,
such as a compound disclosed in U.S. Pat. Nos. 6,130,333,
6,566,360, 6,362,178, or 6,582,351, US20050070541, or
US20040067945; or a compound described in U.S. Pat. Nos. 6,825,197,
6,943,166, 5,981,527, 6,576,644, 5,859,009, 6,943,253, 6,864,253,
5,869,516, 5,488,055, 6,140,329, 5,859,006, or 6,143,777, WO
96/16644, WO 01/19802, WO 96/26940, Dunn, Org. Proc. Res. Dev., 9:
88-97 (2005), or Bi et al., Bioorg Med Chem Lett., 11(18):2461-4
(2001).
[0243] In some embodiments, a reported PDE5 inhibitor is zaprinast;
MY-5445; dipyridamole; vinpocetine; FR229934;
1-methyl-3-isobutyl-8-(methylamino)xanthine; furazlocillin;
Sch-51866; E4021; GF-196960; IC-351; T-1032; sildenafil; tadalafil;
vardenafil; DMPPO; RX-RA-69; KT-734; SKF-96231; ER-21355;
BF/GP-385; NM-702; PLX650; PLX134; PLX369; PLX788; or
vesnarinone.
[0244] In some embodiments, the reported PDE5 inhibitor is
sildenafil or a related compound disclosed in U.S. Pat. Nos.
5,346,901, 5,250,534, or 6,469,012; tadalafil or a related compound
disclosed in U.S. Pat. Nos. 5,859,006, 6,140,329, 6,821,975, or
6,943,166; or vardenafil or a related compound disclosed in U.S.
Pat. No. 6,362,178.
[0245] Non-limiting examples of a reported PDE6 inhibitor useful in
a combination or method described herein include dipyridamole or
zaprinast.
[0246] Non-limiting examples of a reported PDE7 inhibitor for use
in the combinations and methods described herein include BRL 50481;
PLX369; PLX788; or a compound described in U.S. Pat. Nos.
6,818,651; 6,737,436, 6,613,778, 6,617,357; 6,146,876, 6,838,559,
or 6,884,800, US20050059686; US20040138279; US20050222138;
US20040214843; US20040106631; US 20030045557; US 20020198198;
US20030162802, US20030092908, US 20030104974; US20030100571;
20030092721; or US20050148604.
[0247] A non-limiting examples of a reported inhibitor of PDE8
activity is dipyridamole.
[0248] Non-limiting examples of a reported PDE9 inhibitor useful in
a combination or method described herein include SCH-51866; IBMX;
or BAY 73-6691.
[0249] Non-limiting examples of a PDE10 inhibitor include
sildenafil; SCH-51866; papaverine; Zaprinast; Dipyridamole; E4021;
Vinpocetine; EHNA; Milrinone; Rolipram; PLX107; or a compound
described in U.S. Pat. No. 6,930,114, US20040138249, or
US20040249148.
[0250] Non-limiting examples of a PDE11 inhibitor includes IC-351
or a related compound described in WO 9519978; E4021 or a related
compound described in WO 9307124; UK-235,187 or a related compound
described in EP 579496; PLX788; Zaprinast; Dipyridamole; or a
compound described in US20040106631 or Maw et al., Bioorg Med Chem
Lett. 2003 Apr. 17; 13(8):1425-8.
[0251] In some embodiments, the reported PDE inhibitor is a
compound described in U.S. Pat. Nos. 5,091,431, 5,081,242,
5,066,653, 5,010,086, 4,971,972, 4,963,561, 4,943,573, 4,906,628,
4,861,891, 4,775,674, 4,766,118, 4,761,416, 4,739,056, 4,721,784,
4,701,459, 4,670,434, 4,663,320, 4,642,345, 4,593,029, 4,564,619,
4,490,371, 4,489,078, 4,404,380, 4,370,328, 4,366,156, 4,298,734,
4,289,772, RE30,511, 4,188,391, 4,123,534, 4,107,309, 4,107,307,
4,096,257, 4,093,617, 4,051,236, or 4,036,840.
[0252] In some embodiments, the reported PDE inhibitor inhibits
dual-specificity PDE.
[0253] Non-limiting examples of a dual-specificity PDE inhibitor
useful in a combination or method described herein include a
cAMP-specific or cGMP-specific PDE inhibitor described herein;
MMPX; KS-505a; W-7; a phenothiazine; Bay 60-7550 or a related
compound described in Boess et al., Neuropharmacology,
47(7):1081-92 (2004); UK-235,187 or a related compound described in
EP 579496; or a compound described in U.S. Pat. Nos. 6,930,114 or
4,861,891, US20020132754, US20040138249, US20040249148,
0520040106631, WO 951997, or Maw et al., Bioorg Med Chem Lett. 2003
Apr. 17; 13(8):1425-8.
[0254] In some embodiments, a reported PDE inhibitor exhibits
dual-selectivity, being substantially more active against two PDE
isozymes relative to other PDE isozymes. For example, in some
embodiments, a reported PDE inhibitor is a dual PDE4/PDE7
inhibitor, such as a compound described in US20030104974; a dual
PDE3/PDE4 inhibitor, such as zardaverine, tolafentrine,
benafentrine, trequinsine, Org-30029, L-686398, SDZ-ISQ-844,
Org-20241, EMD-54622, or a compound described in U.S. Pat. Nos.
5,521,187, or 6,306,869; or a dual PDE1/PDE4 inhibitor, such as
KF19514
(5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4
(5H)-one).
[0255] The combination of the muscarinic agent donepezil with
enoximone resulted in synergistic activity (see Example 8 below).
Donepezil alone has an EC.sub.50 of 2.02 .mu.M for neuronal
differentiation. Enozimone alone has an EC.sub.50 of 6.76 .mu.M.
The concentration of each agent in combination to reach 50%
activity in neuronal differentiation is 0.78 .mu.M, resulting in a
CI of 0.55, As the CI is less than 1, the two compounds have a
synergistic effect in neuronal differentiation.
[0256] Furthermore, the neurogenic agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported neurosteroid. Non-limiting examples of such a neurosteroid
include pregnenolone and allopregnenalone.
[0257] Alternatively, the neurogenic sensitizing agent may be a
reported non-steroidal anti-inflammatory drug (NSAID) or an
anti-inflammatory mechanism targeting agent in general.
Non-limiting examples of a reported NSAID include a cyclooxygenase
inhibitor, such as indomethacin, ibuprofen, celecoxib, cofecoxib,
naproxen, or aspirin.
[0258] In additional embodiments, the neurogenic agent in
combination with a muscarinic agent, such as an inhibitor of AChE
activity, may be a reported agent for treating migraines.
Non-limiting examples of such an agent include a triptan, such as
almotriptan or almotriptan malate; naratriptan or naratriptan
hydrochloride; rizatriptan or rizatriptan benzoate; sumatriptan or
sumatriptan succinate; zolmatriptan or zolmitriptan, frovatriptan
or frovatriptan succinate; or eletriptan or eletriptan
hydrobromide. Embodiments of the disclosure may exclude
combinations of triptans and an SSRI or SNRI that result in life
threatening serotonin syndrome.
[0259] Other non-limiting examples include an ergot derivative,
such as dihydroergotamine or dihydroergotamine mesylate, ergotamine
or ergotamine tartrate; diclofenac or diclofenac potassium or
diclofenac sodium; flurbiprofen; amitriptyline; nortriptyline;
divalproex or divalproex sodium; propranolol or propranolol
hydrochloride; verapamil; methysergide (CAS RN 361-37-5);
metoclopramide; prochlorperazine (CAS RN 58-38-8); acetaminophen;
topiramate; GW274150
([2-[(1-iminoethyl)amino]ethyl]-L-homocysteine); or ganaxalone (CAS
RN 38398-32-2).
[0260] Additional non-limiting examples include a COX-2 inhibitor,
such as Celecoxib.
[0261] In other embodiments, the neurogenic agent in combination
with a muscarinic agent, such as an inhibitor of AChE activity, may
be a reported modulator of a nuclear hormone receptor. Nuclear
hormone receptors are activated via ligand interactions to regulate
gene expression, in some cases as part of cell signaling pathways.
Non-limiting examples of a reported modulator include a
dihydrotestosterone agonist such as dihydrotestosterone; a
2-quinolone like LG121071
(4-ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]-quinoli-
ne); a non-steroidal agonist or partial agonist compound described
in U.S. Pat. No. 6,017,924; LGD2226 (see WO 01/16108, WO 01/16133,
WO 01/16139, and Rosen et al. "Novel, non-steroidal, selective
androgen receptor modulators (SARMs) with anabolic activity in bone
and muscle and improved safety profile." J Musculoskelet Neuronal
Interact. 2002 2(3):222-4); or LGD2941 (from collaboration between
Ligand Pharmaceuticals Inc. and TAP Pharmaceutical Products
Inc.).
[0262] Additional non-limiting examples of a reported modulator
include a selective androgen receptor modulator (SARM) such as
andarine, ostarine, prostarin, or andromustine (all from GTx,
Inc.); bicalutamide or a bicalutamide derivative such as GTx-007
(U.S. Pat. No. 6,492,554); or a SARM as described in U.S. Pat. No.
6,492,554.
[0263] Further non-limiting examples of a reported modulator
include an androgen receptor antagonist such as cyproterone,
bicalutamide, flutamide, or nilutamide; a 2-quinolone such as
LG120907, represented by the following structure
##STR00001##
[0264] or a derivative compound represented by the following
structure
##STR00002##
[0265] (see Allan et al. "Therapeutic androgen receptor ligands"
Nucl Recept Signal 2003; 1: e009); a phthalamide, such as a
modulator as described by Miyachi et al. ("Potent novel
nonsteroidal androgen antagonists with a phthalimide skeleton."
Bioorg. Med. Chem. Lett. 1997 7:1483-1488); osaterone or osaterone
acetate; hydroxyflutamide; or a non-steroidal antagonist described
in U.S. Pat. No. 6,017,924.
[0266] Other non-limiting examples of a reported modulator include
a retinoic acid receptor agonist such as all-trans retinoic acid
(Tretinoin); isotretinoin (13-cis-retinoic acid); 9-cis retinoic
acid; bexarotene; TAC-101
(4-[3,5-bis(trimethylsilyl)benzamide]benzoic acid); AC-261066 (see
Lund et al. "Discovery of a potent, orally available, and
isoform-selective retinoic acid beta2 receptor agonist." J Med
Chem. 2005 48(24):7517-9); LGD1550
((2E,4E,6E)-3-methyl-7-(3,5-di-ter-butylphen-yl)octatrienoic acid);
E6060 (E6060
[4-{5-[7-fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrol-
yl}benzoic acid]; agonist 1 or 2 as described by Schapira et al.
("In silico discovery of novel Retinoic Acid Receptor agonist
structures." BMC Struct Biol, 2001; 1:1 (published online 2001 Jun.
4) where "Agonist 1 was purchased from Bionet Research (catalog
number 1G-433S). Agonist 2 was purchased from Sigma-Aldrich (Sigma
Aldrich library of rare chemicals. Catalog number S08503-1"); a
synthetic acetylenic retinoic acid, such as AGN 190121 (CAS RN:
132032-67-8), AGN 190168 (or Tazarotene or CAS RN 118292-40-3), or
its metabolite AGN 190299 (CAS RN 118292-41-4); Etretinate;
acitretin; an acetylenic retinoate, such as AGN 190073 (CAS
132032-68-9), or AGN 190089 (or 3-Pyridinecarboxylic acid,
6-(4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-1-ynyl)-, ethyl
ester or CAS RN 116627-73-7).
[0267] In further embodiments, the additional agent for use in
combination with a muscarinic agent may be a reported modulator be
selected from thyroxin, tri-iodothyronine, or levothyroxine.
[0268] Alternatively, the additional agent is a vitamin D
(1,25-dihydroxyvitamine D.sub.3) receptor modulator, such as
calcitriol or a compound described in Ma et al. ("Identification
and characterization of noncalcemic, tissue-selective,
nonsecosteroidal vitamin D receptor modulators." J Clin Invest.
2006 116(4):892-904) or Molnar et al. ("Vitamin D receptor agonists
specifically modulate the volume of the ligand-binding pocket." J
Biol Chem. 2006 281(15):10516-26) or Milliken et al. ("EB1089, a
vitamin D receptor agonist, reduces proliferation and decreases
tumor growth rate in a mouse model of hormone-induced mammary
cancer." Cancer Lett. 2005 229(2):205-15) or Yee et al. ("Vitamin D
receptor modulators for inflammation and cancer." Mini Rev Med
Chem. 2005 5(8):761-78) or Adachi et al. "Selective activation of
vitamin D receptor by lithocholic acid acetate, a bile acid
derivative." J Lipid Res. 2005 46(1):46-57).
[0269] Furthermore, the additional agent may be a reported cortisol
receptor modulator, such as methylprednisolone or its prodrug
methylprednisolone suleptanate; PI-1020 (NCX-1020 or
budesonide-21-nitrooxymethylbenzoate); fluticasone furoate;
GW-215864; betamethasone valerate; beclomethasone; prednisolone; or
BVT-3498 (AMG-311).
[0270] Alternatively, the additional agent may be a reported
aldosterone (or mineralocorticoid) receptor modulator, such as
Spironolactone or Eplerenone.
[0271] In other embodiments, the additional agent may be a reported
progesterone receptor modulator such as Asoprisnil (CAS RN
199396-76-4); mesoprogestin or J1042; J956; medroxyprogesterone
acetate (MPA); R5020; tanaproget; trimegestone; progesterone;
norgestomet; melengestrol acetate; mifepristone; onapristone;
ZK137316; ZK230211 (see Fuhrmann et al. "Synthesis and biological
activity of a novel, highly potent progesterone receptor
antagonist." J Med Chem. 2000 43(26):5010-6); or a compound
described in Spitz "Progesterone antagonists and progesterone
receptor modulators: an overview." Steroids 2003
68(10-13):981-93.
[0272] In further embodiments, the additional agent may be a
reported i) peroxisome proliferator-activated receptor agonist such
as muraglitazar; tesaglitazar; reglitazar; GW-409544 (see Xu et al.
"Structural determinants of ligand binding selectivity between the
peroxisome proliferator-activated receptors." Proc Natl Acad Sci
USA. 2001 98(24):13919-24); or DRL 11605 (Dr. Reddy's
Laboratories); ii) a peroxisome proliferator-activated receptor
alpha agonist like clofibrate; ciprofibrate; fenofibrate;
gemfibrozil; DRF-10945 (Dr. Reddy's Laboratories); iii) a
peroxisome proliferator-activated receptor delta agonist such as
GW501516 (CAS RN 317318-70-0); or iv) a peroxisome
proliferator-activated gamma receptor agonist like a
hydroxyoctadecadienoic acid (HODE); a prostaglandin derivatives,
such as 15-deoxy-Delta12,14-prostaglandin J2; a thiazolidinedione
(glitazone), such as pioglitazone, troglitazone; rosiglitazone or
rosiglitazone maleate; ciglitazone; Balaglitazone or DRF-2593; AMG
131 (from Amgen); or G1262570 (from GlaxoWellcome).
[0273] In additional embodiments, the additional agent may be a
reported modulator of an "orphan" nuclear hormone receptor.
Embodiments include a reported modulator of a liver X receptor,
such as a compound described in U.S. Pat. No. 6,924,311; a
farnesoid X receptor, such as GW4064 as described by Maloney et al.
("Identification of a chemical tool for the orphan nuclear receptor
FXR." J Med Chem. 2000 43(16):2971-4); a RXR receptor; a CAR
receptor, such as 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
(TCPOBOP); or a PXR receptor, such as SR-12813 (tetra-ethyl
2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate).
[0274] The combination of the muscarinic agent tacrine with
rosiglitazone resulted in synergistic activity (see Example 8
below). Tacrine alone has an EC.sub.50 of 8.0 .mu.M for neuronal
differentiation. Rosiglitazone alone has an EC.sub.50 of 0.94
.mu.M. The concentration of each agent in combination to reach 50%
activity in neuronal differentiation is 0.53 .mu.M, resulting in a
CI of 0.67. As the CI is less than 1, the two compounds have a
synergistic effect in neuronal differentiation.
[0275] In additional embodiments, the agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, is ethyl
eicosapentaenoate or ethyl-EPA (also known as
5,8,11,14,17-eicosapentaenoic acid ethyl ester or miraxion, CAS RN
86227-47-6), docosahexaenoic acid (DHA), or a retinoid acid drug.
As an additional non-limiting example, the agent may be Omacor, a
combination of DHA and EPA, or idebenone (CAS RN 58186-27-9).
[0276] In further embodiments, a reported nootropic compound may be
used as an agent in combination with a muscarinic agent, such as an
inhibitor of AChE activity. Non-limiting examples of such a
compound include Piracetam (Nootropil), Aniracetam, Oxiracetam,
Pramiracetam, Pyritinol (Enerbol), Ergoloid mesylates (Hydergine),
Galantamine, Selegiline, Centrophenoxine (Lucidril), Desmopressin
(DDAVP), Nicergoline, Vinpocetine, Picamilon, Vasopressin,
Milacemide, FK-960, FK-962, levetiracetam, nefiracetam, or
hyperzine A (CAS RN: 102518-79-6).
[0277] Additional non-limiting examples of such a compound include
anapsos (CAS RN 75919-65-2), nebracetam (CAS RN 97205-34-0 or
116041-13-5), metrifonate, ensaculin (or CAS RN 155773-59-4 or
KA-672) or ensaculin HCl, Rokan (CAS RN 122933-57-7 or EGb 761),
AC-3933
(5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro--
1,6-naphthyridine) or its hydroxylated metabolite SX-5745
(3-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-2-oxo-1,2-d-
ihydro-1,6-naphthyridine), JTP-2942 (CAS RN 148152-77-6),
sabeluzole (CAS RN 104383-17-7), ladostigil (CAS RN 209394-27-4),
choline alphoscerate (CAS RN 28319-77-9 or Gliatilin), Dimebon (CAS
RN 3613-73-8), tramiprosate (CAS RN 3687-18-1), omigapil (CAS RN
181296-84-4), cebaracetam (CAS RN 113957-09-8), fasoracetam (CAS RN
110958-19-5), PD-151832 (see Jaen et al. "In vitro and in vivo
evaluation of the subtype-selective muscarinic agonist PD 151832."
Life Sci. 1995 56(11-12):845-52), Vinconate (CAS RN 70704-03-9),
PYM-50028 PYM-50028 (Cogane) or PYM-50018 (Myogane) as described by
Harvey ("Natural Products in Drug Discovery and Development. 27-28
Jun. 2005, London, UK." IDrugs. 2005 8(9):719-21), SR-46559A
(3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl),
dihydroergocristine (CAS RN 17479-19-5), dabelotine (CAS RN
118976-38-8), zanapezil (CAS RN 142852-50-4).
[0278] Further non-limiting examples include NBI-113 (from
Neurocrine Biosciences, Inc.), NDD-094 (from Novartis), P-58 or P58
(from Pfizer), or SR-57667 (from Sanofi-Synthelabo).
[0279] Moreover, an agent in combination with a muscarinic agent,
such as an inhibitor of AChE activity, may be a reported modulator
of the nicotinic receptor. Non-limiting examples of such a
modulator include nicotine, acetylcholine, carbamylcholine,
epibatidine, ABT-418 (structurally similar to nicotine, with an
ixoxazole moiety replacing the pyridyl group of nicotine),
epiboxidine (a structural analogue with elements of both
epibatidine and ABT-418), ABT-594 (azetidine analogue of
epibatidine), lobeline, SSR-591813, represented by the following
formula
##STR00003##
or SIB-1508 (altinicline).
[0280] In additional embodiments, an agent used in combination with
a muscarinic agent, such as an inhibitor of AChE activity, is a
reported aromatase inhibitor. Reported aromatase inhibitors
include, but are not limited to, nonsteroidal or steroidal agents.
Non-limiting examples of the former, which inhibit aromatase via
the heme prosthetic group, include anastrozole (Arimidex.RTM.),
letrozole (Femara.RTM.), or vorozole (Rivisor). Non-limiting
examples of steroidal aromatase inhibitors AIs, which inactivate
aromatase, include, but are not limited to, exemestane
(Aromasin.RTM.), androstenedione, or formestane (lentaron).
[0281] Additional non-limiting examples of a reported aromatase for
use in a combination or method as disclosed herein include
aminoglutethimide, 4-androstene-3,6,17-trione (or "6-OXO"), or
zoledronic acid or Zometa (CAS RN 118072-93-8).
[0282] Further embodiments include a combination of a muscarinic
agent, such as an inhibitor of AChE activity, and a reported
selective estrogen receptor modulator (SERM) may be used as
described herein. Non-limiting examples include tamoxifen,
raloxifene, toremifene, clomifene, bazedoxifene, arzoxifene, or
lasofoxifene.
[0283] In other embodiments, a combination of a muscarinic agent,
such as an inhibitor of AChE activity, and a reported cannabinoid
receptor modulator may be used as described herein. Non-limiting
examples include synthetic cannabinoids, endogenous cannabinoids,
or natural cannabinoids. In some embodiments, the reported
cannabinoid receptor modulator is rimonabant (SR141716 or
Acomplia), nabilone, levonantradol, marinol, or sativex (an extract
containing both THC and CBD). Non-limiting examples of endogenous
cannabinoids include arachidonyl ethanolamine (anandamide); analogs
of anandamide, such as docosatetraenylethanolamide or
homo-.gamma.-linoenylethanolamide; N-acyl ethanolamine signalling
lipids, such as the noncannabimimetic palmitoylethanolamine or
oleoylethanolamine; or 2-arachidonyl glycerol. Non-limiting
examples of natural cannabinoids include tetrahydrocannabinol
(THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG),
cannabichromene (CBC), cannabicyclol (CBL), cannabivarol (CBV),
tetrahydrocannabivarin (THCV), cannabidivarin (CBDV),
cannabichromevarin (CBCV), cannabigerovarin (CBGV), or cannabigerol
monoethyl ether (CBGM).
[0284] In yet further embodiments, an agent used in combination
with a muscarinic agent, such as an inhibitor of AChE activity, is
a reported FAAH (fatty acid amide hydrolase) inhibitor.
Non-limiting examples of reported inhibitor agents include URB597
(3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate); CAY10401
(1-oxazolo[4,5-b]pyridin-2-yl-9-octadecyn-1-one); OL-135
(1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane); anandamide (CAS RN
94421-68-8); AA-5-HT (see Bisogno et al. "Arachidonoylserotonin and
other novel inhibitors of fatty acid amide hydrolase." Biochem
Biophys Res Commun. 1998 248(3):515-22); 1-Octanesulfonyl fluoride;
or O-2142 or another arvanil derivative FAAH inhibitor as described
by Di Marzo et al. ("A structure/activity relationship study on
arvanil, an endocannabinoid and vanilloid hybrid." J Pharmacol Exp
Ther. 2002 300(3):984-91).
[0285] Further non-limiting examples include SSR 411298 (from
Sanofi-Aventis), JNJ28614118 (from Johnson & Johnson), or SSR
101010 (from Sanofi-Aventis)
[0286] In additional embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of nitric oxide function. One non-limiting
example is sildenafil (Viagra.RTM.).
[0287] In additional embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of prolactin or a prolactin modulator.
[0288] In additional embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, is a
reported anti-viral agent, with ribavirin and amantadine as
non-limiting examples.
[0289] In additional embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
component of a natural product or a derivative of such a component.
In some embodiments, the component or derivative thereof is in an
isolated form, such as that which is separated from one or more
molecules or macromolecules normally found with the component or
derivative before use in a combination or method as disclosed
herein. In other embodiments, the component or derivative is
completely or partially purified from one or more molecules or
macromolecules normally found with the component or derivative.
Exemplary cases of molecules or macromolecules found with a
component or derivative as described herein include a plant or
plant part, an animal or animal part, and a food or beverage
product.
[0290] Non-limiting examples such a component include folic acid; a
flavinoid, such as a citrus flavonoid; a flavonol, such as
Quercetin, Kaempferol, Myricetin, or Isorhamnetin; a flavone, such
as Luteolin or Apigenin; a flavanone, such as Hesperetin,
Naringenin, or Eriodictyol; a flavan-3-ol (including a monomeric,
dimeric, or polymeric flavanol), such as (+)-Catechin,
(+)-Gallocatechin, (-)-Epicatechin, (-)-Epigallocatechin,
(-)-Epicatechin 3-gallate, (-)-Epigallocatechin 3-gallate,
Theaflavin, Theaflavin 3-gallate, Theaflavin 3'-gallate, Theaflavin
3,3' digallate, a Thearubigin, or Proanthocyanidin; an
anthocyanidin, such as Cyanidin, Delphinidin, Malvidin,
Pelargonidin, Peonidin, or Petunidin; an isoflavone, such as
daidzein, genistein, or glycitein; flavopiridol; a prenylated
chalcone, such as Xanthohumol; a prenylated flavanone, such as
Isoxanthohumol; a non-prenylated chalcone, such as
Chalconaringenin; a non-prenylated flavanone, such as Naringenin;
Resveratrol; or an anti-oxidant neutraceutical (such as any present
in chocolate, like dark chocolate or unprocessed or unrefined
chocolate).
[0291] Additional non-limiting examples include a component of
Gingko biloba, such as a flavo glycoside or a terpene. In some
embodiments, the component is a flavanoid, such as a flavonol or
flavone glycoside, or a quercetin or kaempferol glycoside, or
rutin; or a terpenoid, such as ginkgolides A, B, C, or M, or
bilobalide.
[0292] Further non-limiting examples include a component that is a
flavanol, or a related oligomer, or a polyphenol as described in
US2005/245601AA, US2002/018807AA, US2003/180406AA, US2002/086833AA,
US2004/0236123, WO9809533, or WO9945788; a procyanidin or
derivative thereof or polyphenol as described in US2005/171029AA; a
procyanidin, optionally in combination with L-arginine as described
in US2003/104075AA; a low fat cocoa extract as described in
US2005/031762AA; lipophilic bioactive compound containing
composition as described in US2002/107292AA; a cocoa extract, such
as those containing one or more polyphenols or procyanidins as
described in US2002/004523AA; an extract of oxidized tea leaves as
described in U.S. Pat. Nos. 5,139,802 or 5,130,154; a food
supplement as described in WO 2002/024002.
[0293] Of course a composition comprising any of the above
components, alone or in combination with a muscarinic agent as
described herein is included within the disclosure.
[0294] In additional embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported calcitonin receptor agonist such as calcitonin or the
`orphan peptide` PHM-27 (see Ma et al. "Discovery of novel
peptide/receptor interactions: identification of PHM-27 as a potent
agonist of the human calcitonin receptor." Biochem Pharmacol. 2004
67(7):1279-84). A further non-limiting example is the agonist from
Kemia, Inc.
[0295] In an alternative embodiment, the agent may be a reported
modulator of parathyroid hormone activity, such as parathyroid
hormone, or a modulator of the parathyroid hormone receptor.
[0296] In additional embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may a
reported antioxidant, such as N-acetylcysteine or acetylcysteine;
disufenton sodium (or CAS RN 168021-79-2 or Cerovive); activin (CAS
RN 104625-48-1); selenium; L-methionine; an alpha, gamma, beta, or
delta, or mixed, tocopherol; alpha lipoic acid; Coenzyme Q;
Benzimidazole; benzoic acid; dipyridamole; glucosamine; IRFI-016
(2(2,3-dihydro-5-acetoxy-4,6,7-trimethylbenzofuranyl) acetic acid);
L-carnosine; L-Histidine; glycine; flavocoxid (or LIMBREL);
baicalin, optionally with catechin (3,3',4',5,7-pentahydroxyflavan
(2R,3S form)), and/or its stereo-isomer; masoprocol (CAS RN
27686-84-6); mesna (CAS RN 19767-45-4); probucol (CAS RN
23288-49-5); silibinin (CAS RN 22888-70-6); sorbinil (CAS RN
68367-52-2); spermine; tangeretin (CAS RN 481-53-8); butylated
hydroxyanisole (BHA); butylated hydroxytoluene (BHT); propyl
gallate (PG); tertiary-butyl-hydroquinone (TBHQ);
nordihydroguaiaretic acid (CAS RN 500-38-9); astaxanthin (CAS RN
472-61-7); or an antioxidant flavonoid.
[0297] Additional non-limiting examples include a vitamin, such as
vitamin A (Retinol) or C (Ascorbic acid) or E (including
Tocotrienol and/or Tocopherol); a vitamin cofactors or mineral,
such as Coenzyme Q10 (CoQ10), Manganese, or Melatonin; a carotenoid
terpenoid, such as Lycopene, Lutein, Alpha-carotene, Beta-carotene,
Zeaxanthin, Astaxanthin, or Canthaxantin; a non-carotenoid
terpenoid, such as Eugenol; a flavonoid polyphenolic (or
bioflavonoid); a flavonol, such as Resveratrol, Pterostilbene
(methoxylated analogue of resveratrol), Kaempferol, Myricetin,
Isorhamnetin, a Proanthocyanidin, or a tannin; a flavone, such as
Quercetin, rutin, Luteolin, Apigenin, or Tangeritin; a flavanone,
such as Hesperetin or its metabolite hesperidin, naringenin or its
precursor naringin, or Eriodictyol; a flavan-3-ols
(anthocyanidins), such as Catechin, Gallocatechin, Epicatechin or a
gallate form thereof, Epigallocatechin or a gallate form thereof,
Theaflavin or a gallate form thereof, or a Thearubigin; an
isoflavone phytoestrogens, such as Genistein, Daidzein, or
Glycitein; an anthocyanins, such as Cyanidin, Deiphinidin,
Malvidin, Pelargonidin, Peonidin, or Petunidin; a phenolic acid or
ester thereof, such as Ellagic acid, Gallic acid, Salicylic acid,
Rosmarinic acid, Cinnamic acid or a derivative thereof like ferulic
acid, Chlorogenic acid, Chicoric acid, a Gallotannin, or an
Ellagitannin; a nonflavonoid phenolic, such as Curcumin; an
anthoxanthin, betacyanin, Citric acid, Uric acid, R-.alpha.-lipoic
acid, or Silymarin.
[0298] Further non-limiting examples include
1-(carboxymethylthio)tetradecane;
2,2,5,7,8-pentamethyl-1-hydroxychroman;
2,2,6,6-tetramethyl-4-piperidinol-N-oxyl;
2,5-di-tert-butylhydroquinone; 2-tert-butylhydroquinone;
3,4-dihydroxyphenylethanol; 3-hydroxypyridine; 3-hydroxytamoxifen;
4-coumaric acid; 4-hydroxyanisole; 4-hydroxyphenylethanol;
4-methylcatechol; 5,6,7,8-tetrahydrobiopterin;
6,6'-methylenebis(2,2-dimethyl-4-methanesulfonic
acid-1,2-dihydroquinoline);
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid;
6-methyl-2-ethyl-3-hydroxypyridine; 6-0-palmitoylascorbic acid;
acetovanillone; acteoside; Actovegin; allicin; allyl sulfide;
alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol;
alpha-tocopherol acetate; apolipoprotein A-IV; bemethyl; boldine;
bucillamine; Calcium Citrate; Canthaxanthin; crocetin; diallyl
trisulfide; dicarbine; dihydrolipoic acid; dimephosphon; ebselen;
Efamol; enkephalin-Leu, Ala(2)-Arg(6)-; Ergothioneine; esculetin;
essential 303 forte; Ethonium; etofyllinclofibrate; fenozan;
glaucine; H290-51; histidyl-proline diketopiperazine; hydroquinone;
hypotaurine; idebenone; indole-3-carbinol; isoascorbic acid; kojic
acid, lacidipine, lodoxamide tromethamine; mexidol; morin;
N,N'-diphenyl-4-phenylenediamine;
N-isopropyl-N-phenyl-4-phenylenediamine; N-monoacetylcystine;
nicaraven, nicotinoyl-GABA; nitecapone; nitroxyl; nobiletin;
oxymethacil; p-tert-butyl catechol; phenidone; pramipexol;
proanthocyanidin; procyanidin; prolinedithiocarbamate; Propyl
Gallate; purpurogallin; pyrrolidine dithiocarbamic acid;
rebamipide; retinol palmitate; salvin; Selenious Acid; sesamin;
sesamol; sodium selenate; sodium thiosulfate; theaflavin;
thiazolidine-4-carboxylic acid; tirilazad; tocopherylquinone;
tocotrienol, alpha; a Tocotrienol;
tricyclodecane-9-yl-xanthogenate; turmeric extract; U 74389F; U
74500A; U 78517F; ubiquinone 9; vanillin; vinpocetine;
xylometazoline; zeta Carotene; zilascorb; zinc thionein; or
zonisamide.
[0299] In additional embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of a norepinephrine receptor. Non-limiting
examples include Atomoxetine (Strattera); a norepinephrine reuptake
inhibitor, such as talsupram, tomoxetine, nortriptyline,
nisoxetine, reboxetine (described, e.g., in U.S. Pat. No.
4,229,449), or tomoxetine (described, e.g., in U.S. Pat. No.
4,314,081); or a direct agonist, such as a beta adrenergic
agonist.
[0300] Non-limiting examples of reported adrenergic agonists
include albuterol, clonidine (CAS RN 4205-90-7), yohimbine (CAS RN
146-48-5), arbutamine; befunolol; BRL 26830A; BRL 35135; BRL 37344;
bromoacetylalprenololmenthane; broxaterol; carvedilol; CGP 12177;
cimaterol; cirazoline; CL 316243; Clenbuterol; denopamine;
dexmedetomidine hydrochloride; Dobutamine, dopexamine, Ephedrine,
Epinephrine, Etilefrine; Fenoterol; formoterol; formoterol
fumarate; Hexoprenaline; higenamine; ICI D7114; Isoetharine;
Isoproterenol; Isoxsuprine; levalbuterol tartrate
hydrofluoroalkane; lidamidine; mabuterol; methoxyphenamine;
modafinil; Nylidrin; Orciprenaline; Oxyfedrine; pirbuterol;
Prenalterol; Procaterol; ractopamine; reproterol; Ritodrine; Ro
363; salmeterol; salmeterol xinafoate; SR 58611A; Terbutaline;
tetramethylpyrazine; tizanidine hydrochloride; Tretoquinol;
tulobuterol; Xamoterol; or zinterol.
[0301] In further embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of carbonic anhydrase. Non-limiting examples of
such an agent include acetazolamide, benzenesulfonamide,
Benzolamide, brinzolamide, Dichlorphenamide, dorzolamide,
Ethoxzolamide, Flurbiprofen, Mafenide, Methazolamide, sezolamide,
zonisamide, bendroflumethiazide, benzthiazide, chlorothiazide,
cyclothiazide, dansylamide, diazoxide, ethinamate, furosemide,
hydrochlorothiazide, hydroflumethiazide, mercuribenzoic acid,
methyclothiazide, topiramate, or trichloromethazide.
[0302] In yet additional embodiments, an agent in combination with
a muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of COMT, such as floproprion, or a
catechol-O-methyltransferase (COMT) inhibitor, such as tolcapone
(CAS RN 134308-13-7), nitecapone (CAS RN 116313-94-1), or
entacapone(CAS RN 116314-67-1 or 130929-57-6).
[0303] In yet further embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of hedgehog activity such as cyclopamine,
jervine, lovastatin, ezetimibe, Regadenoson (CAS RN 313348-27-5, or
CVT-3146), a compound described in U.S. Pat. No. 6,683,192 or
identified as described in U.S. Pat. No. 7,060,450, or CUR-61414 or
another compound described in U.S. Pat. No. 6,552,016.
[0304] In other embodiments, an agent in combination with a
muscarinic agent, such as an inhibitor of AChE activity, may be a
reported modulator of IMPDH, such as mycophenolic acid or
mycophenolate mofetil (CAS RN 128794-94-5).
[0305] Other non-limiting examples of an agent in combination with
a muscarinic agent, such as an inhibitor of AChE activity, include
acamprosate (CAS RN 77337-76-9), a growth factor, octreotide (CAS
RN 83150-76-9), modafinil, minocycline or metformin.
[0306] Of course a further combination therapy may also be that of
a muscarinic agent, such as an inhibitor of AChE activity, with a
non-chemical based therapy. Non-limiting examples include the use
of psychotherapy for the treatment of many conditions described
herein, such as the psychiatric conditions, as well as behavior
modification therapy such as that use in connection with a weight
loss program.
[0307] Having now generally described the invention, the same will
be more readily understood through reference to the following
examples which are provided by way of illustration, and are not
intended to be limiting of the present invention, unless
specified.
Examples
[0308] The following examples are offered to illustrate, but not to
limit the claimed invention.
Example 1
Effect on Neuronal Differentiation of Human Neural Stem Cells
[0309] Human neural stem cells (hNSCs) were isolated and grown in
monolayer culture, plated, treated with varying concentrations of
sabcomeline (test compound), and stained with TUJ-1 antibody, as
described in U.S. Provisional Application No. 60/697,905
(incorporated by reference). Mitogen-free test media with 5 .mu.M
DHEA served as a positive control for neuronal differentiation, and
basal media without growth factors served as a negative control.
Results are shown in FIG. 1.
Example 2
Effect on Astrocyte Differentiation of hNSCs
[0310] Experiments were carried out as described in Example 1,
except the positive control for astrocyte differentiation contained
mitogen-free test media with 50 ng/ml BMP-2, 50 ng/ml: LIF and 0.5%
FBS, and cells were stained with GFAP antibody. Results are shown
in FIG. 2.
Example 3
Toxic/Trophic Effect on Human Neural Stem Cells
[0311] Experiments were carried out as described in Example 1,
except that the positive control contained basal media only, and
cells were stained with nuclear dye (Hoechst 33342. Results are
shown in FIG. 3.
Example 4
Proliferation of hNSCs in Neurosphere Culture
[0312] The effect of sabcomeline on the growth rate of hNSCs in
neurosphere culture was determined by measuring the area of
individual neurospheres as a function of time, as described in U.S.
Provisional Application No. 60/697,905 (incorporated by reference).
Results are shown in FIG. 4.
Example 5
Immunohistochemistry with Neuronal and Astrocyte Markers
[0313] Immunohistochemistry was carried out as described in U.S.
Provisional Application No. 60/697,905 (incorporated by
reference).
Example 6
In vivo Chronic Dosing Studies
[0314] Male Fischer F344 rats were treated with 0, 0.01 and 0.05
mg/kg sabcomeline for 28 days. FIG. 12 shows the effect of chronic
dosing of rats with Sabcomeline on the differentiation of neural
progenitor cells into mature neuron within the subgranular zone of
the dentate gyrus. Various characteristics and behavioral responses
in the treated rats were measured as described below.
Locomotor Activity
[0315] Open field activity during the light phase of the diurnal
cycle is quantified via photoelectric cell monitoring in a
Plexiglas cube open-field arena (45 cm.times.45 cm.times.50 cm high
with infra-red (I/R) array, Hamilton-Kinder San Diego, Calif.).
Measurements were collected for 30 mins (6 blocks of 5 min):
ambulatory distance in center and periphery; ambulatory time in
center and periphery; total time in center and periphery; rearing
in center and periphery; the number of zone entries; and total
distance. Testing began 30 minutes after Sabcomeline injection.
Body Weight
[0316] Rats were weighed daily.
Forced Swim Test
[0317] Active motor behavior is measured in a swim tank, this test
being a modification of that described by Porsolt, R. D., Bertin,
A., Jalfree, M. Arch. Int. Pharmacodyn Ther. 229 (1977) 327-336.
The animal is placed into the swim tank (38 cm deep). The swim test
consists of two phases; a 15 minute pretest and a 5 minute test
24-hours later. Activity is quantified by measuring three aspects
of behavior: (1) immobility, defined as an absence of movement
other than what is required to remain afloat, (2) swimming, defined
as horizontal movement greater than what is required to remain
afloat and (3) climbing, vertical movement greater than what is
required to remain afloat. The predominant behavior is scored every
5 seconds by trained observers for a total of 5 minutes.
Novelty Suppressed Feeding Assay
[0318] Twenty-four hours prior to behavioral testing, all food is
removed from the home cage. At the time of testing a single pellet
is placed in the center of a novel arena. Animals are placed in the
corner of the arena and latency to eat the pellet is recorded.
Compounds are generally administered 30 minutes prior to testing.
Animals receive compound daily for 21 days and testing is performed
on day 21. A decreased latency to eat the food pellet is indicative
of both neurogenesis and antidepressant activity.
[0319] Novel Object Recognition Assay
[0320] The apparatus consisted of an open field
(45.times.45.times.50 cm high) made of polycarbonate. Triplicate
copies were used of the objects to be discriminated. Care was taken
to ensure that the pair of objects tested were made from the same
material so that they could not be distinguished readily by
olfactory cues although they had very different appearances. Each
test session consisted of two phases. In the initial
familiarization phase, two identical objects (A1 and A2) were
placed in the far corners of the box arena. A rat was then placed
in the middle of the arena and allowed 15 minutes to explore both
objects. Exploration of an object was defined as directing the nose
to the object at a distance of less than 2 cm and/or touching it
with the nose. After a delay, the rat was re-introduced to the
arena ("test phase"). The box now contained a third identical copy
of the familiar object (A3) and a new object (B). These were placed
in the same locations as the sample stimuli, whereby the position
(left or right) of the novel object in the test phase was balanced
between rats. For half the rats, object A was the sample and object
B was the novel alternative. The test phase was 15 minutes in
duration, with the first 30 seconds of object interaction used to
determine preference scores. Any animal with less than 15 seconds
of object exploration were excluded from analysis. FIG. 10 shows
the effect of chronic dosing of rats with sabcomeline on cognitive
performance in a novel object recognition assay.
Example 7
Effect of Acute Dosing on Proliferation of NSCs
[0321] Male Fischer F344 rats are injected with varying doses of
test compound+vehicle or vehicle only (negative control) once daily
for five days, followed by a single intraperitoneal injection with
100 mg/kg BrdU. Rats are then anesthetized and killed by
transcardial perfusion of 4% paraformaldehyde at day 28. Brains
were rapidly removed and stored in 4% paraformaldehyde for 24 hours
and then equilibrated in phosphate buffered 30% sucrose. Free
floating 40 micron sections were collected on a freezing microtome
and stored in cryoprotectant. Antibodies against BrdU and cells
types of interest (e.g., neurons, astrocytes, oligodendrocytes,
endothelial cells) will also be used for detection of cell
differentiation. In brief, tissues were washed (0.01 M PBS),
endogenous peroxidase blocked with 1% hydrogen peroxide, and
incubated in PBS (0.01M, pH 7.4, 10% normal goat serum, 0.5% Triton
X-100) for 2 hours at room temperature. Tissues were then incubated
with primary antibody at 4.degree. C. overnight. The tissues were
rinsed in PBS followed by incubation with biotinylated secondary
antibody (1 hour at room temperature). Tissues were further washed
with PBS and incubated in avidin-biotin complex kit solution at
room temperature for 1 hour. Various fluorophores linked to
streptavidin were used for visualization. Tissues were washed with
PBS, briefly rinsed in dH.sub.2O, serially dehydrated and
coverslipped.
[0322] Cell counting and unbiased stereology was limited to the
hippocampal granule cell layer proper and a 50 um border along the
hilar margin that includes the neurogenic subgranular zone. The
proportion of BrdU cells displaying a lineage-specific phenotype
was determined by scoring the co-localization of cell phenotype
markers with BrdU using confocal microscopy. Split panel and z-axis
analysis were used for all counting. All counts were performed
using multi-channel configuration with a 40.times. objective and
electronic zoom of 2. When possible, 100 or more BrdU-positive
cells were scored for each maker per animal. Each cell was manually
examined in first full "z"-dimension and only those cells for which
the nucleus is unambiguously associated with the lineage-specific
marker were scored as positive. The total number of BrdU-labeled
cells per hippocampal granule cell layer and subgranule zone were
determined using diaminobenzadine stained tissues. Overestimation
was corrected using the Abercrombie method for nuclei with
empirically determined average diameter of 13 um within a 40 um
section. The results, shown in FIG. 11, indicate that sabcomeline
can produce neurogenic effects with a rapid onset of action.
Example 8
Effect of Combined Dosing of Sabcomeline and Fluoxetine on
Antidepressant Activity
[0323] Male Fischer F344 rats are chronically injected with test
compound(s)+vehicle or vehicle only (negative control) once daily,
and assayed in the novelty suppressed feeding assay as described
above in example 6. The results, shown in FIG. 13A, indicate that
the combination of sabcomeline and fluoxetine can produce
antidepressant effects at extremely low doses that are
significantly greater than either compound alone.
Example 9
Effect of Combined Dosing of Sabcomeline and Fluoxetine on
Proliferation of NSCs
[0324] Male Fischer F344 rats are injected with test
compound(s)+vehicle or vehicle only (negative control) once daily
for 28 days. Intraperitoneal injections with 100 mg/kg BrdU occur
daily for 5 days after day 7. Rats are then anesthetized and killed
by transcardial perfusion of 4% paraformaldehyde at day 28, and
proliferating NCS's are measured as described above in Example 7.
The results, shown in FIG. 13B, indicate that the combination of
sabcomeline and fluoxetine results in significant neurogenic
effects at very low doses of compound.
Example 10
Effect of Combining Donepezil and Captopril on Neuronal
Differentiation of Human Neural Stem Cells
[0325] Human neural stem cells (hNSCs) were isolated and grown in
monolayer culture, plated, treated with varying concentrations of
donepezil and/or captopril (test compounds), and stained with TUJ-1
antibody, as described in Example 1.
[0326] Results are shown in FIG. 14, which shows concentration
dependent response curves of neuronal differentiation after
subtraction of background media values. The concentration response
curve of the combination of donepezil and captopril is shown with
the concentration response curves of donepezil or captopril alone.
The data is presented as a percent of neuronal positive control.
The data indicate that the combination of donepezil and captopril
resulted in superior promotion of neuronal differentiation than
either agent alone.
Example 11
Reduction of Buspirone-Induced Astrocyte Differentiation of Human
Neural Stem Cells by Combination with Donepezil
[0327] Human neural stem cells (hNSCs) were isolated and grown in
monolayer culture, plated, treated with varying concentrations of
donepezil and/or buspirone (test compounds), and stained with GFAP
antibody, as described in U.S. Provisional Application No.
60/697,905 (incorporated by reference). Mitogen-free test media
with a positive control for neuronal differentiation was used along
with basal media without growth factors as a negative control.
[0328] Results are shown in FIG. 15, which shows concentration
dependent response curves of astrocyte differentiation after
subtraction of background media values, The concentration response
curve of the combination of donepezil and buspirone is shown with
the concentration response curves of buspirone. The data are
presented as a percent of neuronal positive control. The data
indicate that the combination of donepezil with buspirone
significantly reduced astrocyte differentiation.
Example 12
Determination of Synergy
[0329] The presence of synergy was determined by use of a
combination index (CI). The CI based on the EC.sub.50 as used to
determine whether a pair of compound had an additive, synergistic
(greater than additive), or antagonistic effect when run in
combination. The CI is a quantitative measure of the nature of drug
interactions, comparing the EC.sub.50's of two compounds, when each
is assayed alone, to the EC.sub.50 of each compound when assayed in
combination. The combination index (CI) is equal to the following
formula:
C 1 I C 1 + C 2 I C 2 + ( C 1 * C 2 ) ( I C 1 * I C 2 )
##EQU00001##
[0330] where C1 and C2 are the concentrations of a first and a
second compound, respectively, resulting in 50% activity in
neuronal differentiation when assayed in combination; and IC1 and
IC2 are the concentrations of each compound resulting in 50%
activity when assayed independently. A CI of less than 1 indicates
the presence of synergy; a CI equal to 1 indicates an additive
effect; and a CI greater than 1 indicates antagonism between the
two compounds.
[0331] The combination of the muscarinic agent tacrine with the
5-HT1a receptor agonist buspirone resulted in synergistic activity.
Tacrine alone has an EC.sub.50 of 8.0 .mu.M for neuronal
differentiation. Buspirone alone has an EC.sub.50 of 8.4 .mu.M. The
concentration of each agent in combination to reach 50% activity in
neuronal differentiation is 0.122 .mu.M, resulting in a CI of 0.03
by application of the above formula. As the CI is less than 1, the
two compounds have a synergistic effect in neuronal
differentiation.
[0332] The above is based on the selection of EC.sub.50 as the
point of comparison for the two compounds. The comparison is not
limited by the point used, but rather the same comparison may be
made at another point, such as EC.sub.20, EC.sub.30, E.sub.40,
EC60, EC.sub.70, EC.sub.80, or any other EC value above, below, or
between any of those points.
[0333] All references cited herein, including patents, patent
applications, and publications, are hereby incorporated by
reference in their entireties, whether previously specifically
incorporated or not.
[0334] Having now fully provided the instant disclosure, it will be
appreciated by those skilled in the art that the same can be
performed within a wide range of equivalent parameters,
concentrations, and conditions without departing from the spirit
and scope of the disclosure and without undue experimentation.
[0335] While the disclosure has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications. This application is intended to
cover any variations, uses, or adaptations of the disclosure
following, in general, the disclosed principles and including such
departures from the disclosure as come within known or customary
practice within the art to which the disclosure pertains and as may
be applied to the essential features hereinbefore set forth.
* * * * *