U.S. patent application number 09/320446 was filed with the patent office on 2002-01-31 for glycine site full agonist for treating a psychosis.
Invention is credited to JAVITT, DANIEL C..
Application Number | 20020013364 09/320446 |
Document ID | / |
Family ID | 27358591 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013364 |
Kind Code |
A1 |
JAVITT, DANIEL C. |
January 31, 2002 |
GLYCINE SITE FULL AGONIST FOR TREATING A PSYCHOSIS
Abstract
Process for treating psychosis such as schizophrenia using
glycine-site full agonists or a precursor thereof.
Inventors: |
JAVITT, DANIEL C.;
(RIVERDALE, NY) |
Correspondence
Address: |
SUGHRUE MION ZINN MACPEAK & SEAS PLLC
2100 PENNSYLVANIA AVENUE N W
WASHINGTON
DC
200373213
|
Family ID: |
27358591 |
Appl. No.: |
09/320446 |
Filed: |
May 27, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09320446 |
May 27, 1999 |
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09212273 |
Dec 16, 1998 |
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6162827 |
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09212273 |
Dec 16, 1998 |
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08759714 |
Dec 6, 1996 |
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5854286 |
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Current U.S.
Class: |
514/531 ;
514/458; 514/474; 514/551; 514/561; 514/578; 514/663; 514/762 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/16 20130101; A61K 31/198 20130101 |
Class at
Publication: |
514/531 ;
514/561; 514/551; 514/578; 514/762; 514/663; 514/474; 514/458 |
International
Class: |
A61K 031/355; A61K
031/195; A61K 031/215; A61K 031/22 |
Claims
What is claimed:
1. A process for treating a human patient having a psychosis which
comprises administering to said human a substitute for glycine at
the glycine-site or a precursor of said substitute or a glycine
precursor, in an amount sufficient to potentiate NMDA
receptor-mediated neurotransmission.
2. The process of claim 1 wherein the treatment increases the
patient's glycine CNS level.
3. The process of claim 1 wherein, D-serine or D-alanine is
administered.
4. The process of claim 1 wherein an amino acid, polypeptide or
prodrug which functions as a precursor of glycine synthesis in the
CNS is administered.
5. The process of claim 1 wherein an amino acid, polypeptide or
prodrug which functions as a precursor of D-serine synthesis in the
CNS is administered.
6. The process of claim 1 wherein the psychosis is
schizophrenia.
7. The process of claim 1 wherein a substitute for glycine is
administered.
8. The process of claim 1 wherein a precursor of a substitute for
glycine is administered.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of
prior application Ser. No.09/212,273 filed Dec. 16, 1998, in turn a
divisional application of Ser. No. 08/759,714 filed Dec. 6, 1996
(now U.S. Pat. No. 5,854,286). Priority is claimed from Provisional
application No. 60/008361 filed Dec. 7, 1995. The subject matters
of the prior applications are incorporated in their entirety herein
by reference thereto.
BACKGROUND
[0002] Traditional models of schizophrenia have focused on
dopaminergic systems. More recent models, however, derive from the
phencyclidine (PCP, "angel dust") model of schizophrenia (Javitt,
1987; Javitt and Zukin, 1991) and postulate that schizophrenia is
associated with dysfunction or dysregulation of neurotransmission
mediated at brain N-methyl-D-aspartate (NMDA)-type glutamate
receptors. The PCP/NMDA model of schizophrenia raised the
possibility that agents which augment NMDA receptor-mediated
neurotransmission might be therapeutically beneficial in
schizophrenia. The primary neurotransmitter acting at NMDA
receptors is glutamate. However, NMDA receptor activity is also
modulated by the amino acid glycine which binds to a selective
modulatory site that is an integral component of the NMDA receptor
complex. U.S. Pat. No. 5,854,286 discloses the use of orally
administered glycine, in dietary quantities, for the treatment of
schizophrenia.
[0003] Glycine is considered a full agonist at the NMDA-associated
glycine binding site (McBain et al., 1989). The clinical findings
with glycine detailed in the prior patents U.S. Pat. Nos. 5,854,286
and 5,837,730 applications therefore, provided the first evidence
that glycine-site full agonists are effective in the treatment of
schizophrenia. This concept has also recently been supported by a
study utilizing D-serine (Tsai et al., 1998), an alternative
glycine site full agonist (McBain et al., 1989; Javitt et al.,
1989; Kleckner and Dingledine, 1988; Wong et al., 1987; Reynolds et
al., 1987), consistent with the ability of this compound to induce
glycine-like behavioral effects in rodents (Tanii et al., 1994,
1991) and to penetrate into CNS following peripheral administration
(Hashimoto and Oka, 1997). D-Serine, like glycine, is present in
brain in high concentration and may serve as an endogenous ligand
for the glycine binding site of the NMDA receptor complex (Schell
et al., 1995). The use of D-serine, along with use of other agents
that might substitute for glycine at the glycine site of the NMDA
receptor complex, was disclosed in the above noted U.S. patents and
in Provisional application No. 60/008361 filed Dec. 1, 1995.
[0004] Although the findings with glycine and D-serine support the
use of full glycine-site agonists, others have proposed that
partial agonists at the glycine site, such as the drug
D-cycloserine, should be more effective than full agonists in the
treatment of schizophrenia (Cordi, U.S. Pat. No. 5,187,171).
Partial agonists bind to the same site as full agonists (i.e.,
glycine recognition site of the NMDA receptor complex), but
potentiate channel opening only to a much smaller percent
(typically 40-70% of the activation seen with full agonists, McBain
et al., 1989). Clinical studies with D-cycloserine have provided
support for the concept that partial glycine-site antagonists may
be effective in the treatment of schizophrenia (reviewed in D'Souza
et al., 1995), and, the degree of improvement seen in studies of
D-cycloserine (reviewed in D'Souza et al., 1995) has been
comparable in some circumstances to the degree of improvement
observed following studies with glycine (Heresco-Levy et al., 1996;
Leiderman et al., 1996 and reviewed in D'Souza et al., 1995) or
D-serine (Tsai et al., 1998). No study has yet compared the
effectiveness of glycine treatment to that of D-cycloserine
treatment.
[0005] A second potential approach to augmentation of NMDA
receptor-mediated neurotransmission is the administration of agents
that inhibit glycine transporters in brain, thereby preventing
glycine removal from active sites within CNS. It has been known for
many years that the brain contains active transport systems for
glycine that may regulate brain levels (Debler and Lajtha, 1987;
D'Souza, 1995). More recent studies demonstrated that glycine
transporters are differentially expressed in different brain region
(Liu et al, 1993; Zafra et al., 1995) and may be co-localized with
NMDA receptors (Smith et al., 1992). However, it has also been
known for many years that extracellular glycine levels are beyond
the level needed to saturate the NMDA-associated glycine binding
site, making it unclear whether glycine transporters are, in fact,
able to maintain subsaturating glycine levels in the immediate
vicinity of NMDA receptors. This is a crucial issue in that, if
glycine levels were already at or above saturating levels,
additional glycine would not, on theoretical grounds, be able to
stimulate NMDA functioning (Wood, 1995).
[0006] U.S. Pat. No. 5,837,730, to the current inventor provided
the first evidence that an identified glycine transport inhibitor,
glycyldodecylamide (GDA), was able to exert glycine-like, anti-PCP
behavioral effects in rodents, and thus the first evidence that
glycine transport inhibitors should exert glycine-like amelioration
of negative and cognitive symptoms in schizophrenia. In U.S. Pat.
No. 5,837,730, data were presented from a series of three compounds
demonstrating appropriate rank order of potency of these compounds
in producing glycine-like behavioral effects in rodents.
SUMMARY OF THE INVENTION
[0007] It is therefore unknown whether full agonists at the
glycine-site as a class are more or less effective than partial
agonists, and thus, it is unknown whether glycine site
full-agonists as a class would be more beneficial in the treatment
of persistent negative symptoms of schizophrenia. The present
application provides the first direct comparison of the
effectiveness of full and partial glycine agonists in the treatment
of schizophrenia (Study 1, below). It demonstrates that the full
agonist, glycine, produces significantly greater symptomatic
improvement than the partial agonist D-cycloserine among subjects
who received both treatments in placebo controlled, double blind
trials. This study, therefore, provides the first evidence that
substitutes for glycine at the glycine site (which are full glycine
agonists) as a class, are more effective than partial agonists.
Other glycine substitutes at the glycine site include D-isomers of
serine and alanine (McBain et al., 1989) and optimized derivatives
thereof. Other agents such as glycineamide, threonine or glycine
polypetides or glycine prodrugs are metabolized in brain to
glycine, and should serve as active precursors of glycine and/or
serine in the treatment of schizophrenia. Other amino acids,
prodrugs or polypeptides which serve as precursors for other full
glycine agonists in CNS can be employed. This may be accomplished
by microencapsulation of glycine, for example using liposomes, for
delivery to CNS, or by construction of polyglycine or polyserine
vectors incorporating a CNS targeted moiety chosen to encourage
penetration into CNS.
[0008] In another embodiment, the present inventor can now
demonstrate that the ability of glycine transport inhibitors to
reverse PCP-induced behavioral effects correlates significantly
with their ability to inhibit glycine transport in vitro,
supporting the discovery that such agents exert their glycine-like
behavioral effects by blocking brain glycine transport. A number of
glycylakylamides are tested herein (Study 2).
DETAILED DESCRIPTION
[0009] Study 1--Relative effectiveness of a glycine binding site
full agonist (glycine) and partial agonist (D-cycloserine) in the
treatment of schizophrenia.
[0010] Rationale
[0011] Endogenous dysfunction or dysregulation of neurotransmission
mediated at NMDA-type glutamate receptors may contribute
significantly to the pathophysiology of negative and cognitive
symptoms of schizophrenia. NMDA receptor activation is regulated
not only by glutamate but also by glycine, which mediates its
action at a strychnine-insensitive binding site associated with the
NMDA receptor complex. Glycinergic agents, therefore, may be
therapeutically beneficial in schizophrenia.
[0012] Two potential agents have been suggested as potential agents
for stimulation of NMDA receptor-mediated neurotransmission in
schizophrenia: glycine and D-cycloserine (reviewed in D'Souza et
al., 1995). Glycine is a naturally occurring amino acid and a
normal dietary constituent. Glycine acts as a full agonist at the
NMDA-associated glycine binding site, but must be given at large
(>30 g/day) doses because of its poor permeability across the
blood brain barrier. D-Cycloserine is an anti-tubercular drug that
also functions as a partial agonist at the NMDA-associated glycine
site. D-Cycloserine readily crosses the blood-brain barrier.
However, D-cycloserine is only 40% as effective as glycine in
potentiating NMDA receptor-mediated neurotransmission. Thus, at
high doses, D-cycloserine may act as a functional glycine
antagonist. Both glycine (the present inventor) and D-cycloserine
(D'Souza et al., 1995) are reported to significantly ameliorate
neuroleptic-resistant negative symptoms in schizophrenia. The
relative effectiveness of these two agents, however, has not been
compared.
[0013] Methods
[0014] Seven subjects were identified who participated in each of
two separate studies investigating effects of NMDA augmenting
agents in schizophrenia. The first investigated effects of 0.8
g/kg/day (approx. 60 g/day) glycine. The second study investigated
effects of 50 mg/day D-cycloserine. Separate informed consent was
obtained for each study. Subjects met DSM-IV criteria for
schizophrenia and were free of other Axis I diagnoses (including
substance abuse) or concurrent medical illness. All met criteria
for neuroleptic-resistance, and manifested moderate-to-severe
symptoms despite continuous neuroleptic treatment for at least 3
months. Mean age of the patients upon study entry was 39.9.+-.15.7
yrs (Table 1). Patients had been ill, on average, for 20.1.+-.13.4
yrs. at the time of study entry. Their duration of most recent
hospitalization was 8.5.+-.7.4 yrs.
[0015] Both studies were conducted using a double blind,
placebo-controlled crossover design. Total study length was 16
weeks. Patients underwent an initial 2 week stabilization period,
following by 6 weeks of treatment with either active medication or
placebo. They then underwent a 2-week washout followed by 6 weeks
of crossover treatment. Antipsychotic dose was held constant
throughout each trial. Symptom ratings were performed using the
Positive and Negative Syndrome Scale (PANSS). One patient
discontinued during week 4 of D-cycloserine treatment due to
symptom exacerbation, and was not available for the placebo
treatment arm.
[0016] Statistical analyses (two-tailed) were accomplished using
the SPSS computer program. Pre-vs. post-treatment comparisons were
performed using paired t-tests. Treatment vs. placebo effects were
evaluated using repeated measures ANOVA. Values in text represent
mean .+-. standard deviation.
[0017] Results and Discussion
[0018] At entry into the glycine treatment study, the baseline
negative symptom score for the 7 subjects was 39.0.+-.6.6. During
glycine treatment, subjects experienced an 11.3.+-.3.6 point
reduction in negative symptoms (t=8.21, df=6, p<0.0001),
corresponding to a mean 28.5% reduction in symptoms (FIG. 1). In
contrast, negative symptoms increased by 0.1.+-.1.7 points during
treatment with placebo. The treatment by time interaction was
highly significant (F[1,6]=83.5, p<0.001). Positive symptoms did
not change significantly from beginning (25.7.+-.7.0 points) to end
(22.0.+-.4.0 points) of glycine treatment. However, a significant,
13.0.+-.7.7 point change in general psychopathology from
56.0.+-.19.4 to 43.0.+-.13.8 points was observed (t=4.44, df=6,
p<0.005). This reduction corresponded to a 23.2% decrease in
symptoms.
[0019] Following completion of the double blind glycine treatment
study, subjects included in this report were treated with
antipsychotics alone for a mean duration of 15.6.+-.5.9 mo. (range:
6-23 mo.) before being entered into the D-cycloserine study. The
mean negative symptom score for these subjects upon entry into the
D-cycloserine study, 39.0.+-.7.8, was highly similar to the score
that had been observed prior to glycine treatment. Medications and
doses used during the D-cycloserine trial were similar to those
used during the prior glycine trial (Table 1).
[0020] During D-cyloserine treatment, subjects experienced a
significant, 3.6.+-.3.7 point reduction in negative symptoms
(t=2.56, p<0.05), corresponding to a mean 9.2% decrease in
symptoms. In contrast, the degree of negative symptom reduction
during placebo treatment for these subjects, 1.0.+-.3.1 points ,
was not significant. However, the treatment by time interaction was
not significant (F[1,5]=1.87, p=0.23). Positive symptoms and
general psychopathology scores did not change significantly during
treatment with either D-cycloserine or placebo.
[0021] In order to assess relative effectiveness of glycine and
D-cycloserine for treatment of negative symptoms in these subjects,
negative symptom change scores were compared across the two trials.
The degree of reduction in negative symptoms observed during
glycine treatment was 3-fold greater than that observed during
D-cycloserine treatment. The difference was highly significant
(t=8.2, df=6, p<0.0001). These data provide the first direct
comparison of effects of glycine and D-cycloserine in the same
group of patients, and the first demonstration that the full
agonist glycine is significantly more effective in the treatment of
negative symptoms of schizophrenia than the partial agonist
D-cycloserine. The finding that the full agonist, glycine, is
superior to the partial agonist D-cycloserine suggests that other
full agonists of the glycine site (or precursors thereof) should
also be therapeutically beneficial in schizophrenia. Other
potential agents to be used would include D-serine, D-alanine,
glycineamide, threonine and poplypeptide precursors of such
compounds.
1TABLE 1 Demographic and treatment characteristics of study
patients Glycine study Dose D-Cycloserine study Sub- Gen- (mg/ Dose
ject Age der Medication day) Medication (mg/day) 1 57 M
thioridazine 250 thioridazine 100 2 44 M clozapine 200 clozapine
200 3 24 M thioridazine 50 thioridazine 100 4 49 M clozapine 400
clozapine 400 5 25 M clozapine 450 risperidone 6 6 63 F
chlorpormazine 300 haloperidol 40 7 30 F clozapine 350 clozapine
400
[0022] Experiment #2--Inhibition of PCP-induced hyperactivity by
glycine-transport antagonists
[0023] Rationale
[0024] Earlier double blind, placebo-controlled trials of glycine
in schizophrenia support the idea that NMDA augmenting agents will
be beneficial in the treatment of schizophrenia. See U.S. Pat. No.
5,854,286. The clinical utility of this agent is limited, however,
by the relatively large doses that are required to significantly
elevate CNS glycine levels (Toth and Lajtha, 1986; D'Souza et al.,
1995). The large doses are required because glycine permeates
across the blood-brain barrier slowly by passive diffusion, and,
once in the CNS, is sequestered intracellularly by glycine
transporters . Two families of glycine transporters have been
identified. glycine type 2 (GLYT2) transporters are co-localized
with inhibitory (strychnine-sensitive) glycine receptors in
hindbrain and spinal cord and maintain low glycine levels within
the synaptic cleft in those brain regions. In contrast, type 1
transporters (GLYT1) are co-localized with NMDA receptors in
forebrain and hippocampus, and may serve to maintain low
intrasynaptic glycine levels specifically in the local region
around NMDA receptors. It is possible, therefore, that inhibition
of GLYT1 transporters would lead to elevations of glycine levels in
the immediate vicinity of NMDA receptors and augmentation of NMDA
receptor-mediated neurotransmission without requiring
administration of exogenous glycine. Support for such a hypothesis
comes from a recent study in which co-expression of GLYT1
transporters along with NMDA receptors in Xenopus oocytes led to
significant inhibition of NMDA receptor responsiveness (Supplison
and Bergman, 1996). Blockade of GLYT1 transporters would thus
theoretically be expected to exert an opposite effect. The use of
glycine transport blockers to augment NMDA receptor-mediated
neurotransmission would be analogous to the use of
noradrenaline/serotonin reuptake inhibitors (rather than precursors
such as tyrosine or tryptophan) to enhance monoaminergic
neurotransmission.
[0025] In early preclinical studies investigating effects of
glycine on PCP-induced hyperactivity, it was noted that a specific
glycine derivative, GDA, was significantly more potent than glycine
itself in reversing PCP-induced hyperactivity (Toth et al., 1986).
Although the mechanism of action of GDA was unknown at the time of
those initial studies, more recent research has demonstrated that
GDA acts as a glycine transport inhibitor at doses similar to those
used in behavioral studies (U.S. Pat. No. 5,837,730); Javitt and
Frusciante, 1997; Javitt et al., 1997). To the extent that the
behavioral effects of GDA are due to its inhibition of glycine
transport, the ability of GDA to antagonize PCP-induced
hyperactivity supports the concept that glycine transport
inhibitors, particularly those acting at GLYT1 transporters, may be
useful in the treatment of schizophrenia. However, because GDA may
have idiosyncratic effects unrelated to its effects at the glycine
transport site, it is important to test additional compounds with
known affinity for glycine transporters. For this study, several
novel GDA-related compounds were synthesized and their effects on
PCP-induced hyperactivity and in vitro glycine transport were
characterized. These compounds were structurally similar to GDA,
but differed in the length of the carbon sidechain that was joined
to the glycine backbone via the amide linkage. The length of carbon
chain varied from 6 to 13 carbon atoms. The 6-carbon analog (G6A)
was found in one early study not to significantly inhibit
PCP-induced hyperactivity (Toth et al., 1986). The other agents
(G8A, G10A, G11A and G13A) had not been synthesized previously.
[0026] Methods
[0027] Glycineamide derivatives were synthesized in house according
to the approach of Toth et al (1986). The specific agents used for
study were glycylhexylamide (G6A), glycyloctylamide (G8A),
glycyldecylamide (G10A), glycylundecylamide (G11A) and
glycyltriscadecylamide (G13A).
[0028] Behavioral studies were performed using BALB/c mice (25 g)
of either sex. Rodent activity was monitored using a
photocell-based activity meter (Columbus Instruments Auto-Track
System, Columbus, Ohio). Animals were placed in test cages and
allowed to accommodate overnight. On the day of experiment,
animals, in their home cages, were placed on the activity monitors
and baseline activity was monitored for 20 min., after which time
animals were pretreated with either saline or a specified
glycineamide derivative ( 0.1 g/kg i.p.). 30 min. after
pretreatment, animals were injected with either PCP (5 mg/kg i.p.)
or amphetamine (5 mg/kg s.c.). Activity was then monitored for an
additional 90 minutes. For statistical analyses, summed activity
over the 90 min. following PCP/amphetamine injection was used as a
measure of drug-induced hyperactivity.
[0029] Synaptosomal P.sub.2 fractions were prepared from cerebral
cortex+hippocampus of Sprague-Dawley rats (200-250 g). Brain tissue
was homogenized in 0.32 M sucrose in Tris-HCl buffer (pH 7.4), and
centrifuged at 1,000.times.g for 10 min at 4.degree. C. in a
Sorvall 5C centrifuge. The supernatant was then centrifuged at
14,000.times.g for 10 min and the pellet resuspended in artificial
CSF having the following composition (mM): NaCl, 125; KCl, 3;
MgSO.sub.4, 1.2; CaCl.sub.2, 1.2; NaH.sub.2PO.sub.4, 1;
NaHCO.sub.3, 22; glucose, 10. Homogenate was aerated with 95%
O.sub.2/5% CO.sub.2 until use. 1 ml aliquots of homogenate were
preincubated with specific concentrations of glycineamide
derivatives, following which incubation was initiated by the
addition of 10 .mu.l of 10 .mu.M [.sup.3H]glycine (DuPont/NEN or
Sigma, spec. act. .apprxeq.45 Ci/mmol) to obtain a final
concentration of 100 nM. Nonspecific binding was determined in the
presence of 10 mM sarcosine. Following 5 min, incubation was
terminated by filtration under reduced pressure using a Brandel
24-well cell harvester and Whatman GF-B filters. Radioactivity was
determined by scintillation counter with approximate efficiency of
50%.
[0030] Results
[0031] In prior studies, GDA has been found to inhibit PCP-induced
hyperactivity at doses of 50-200 mg/kg i.p. For the present study,
an initial experiment evaluated the specificity of the GDA effect.
Rats were pre-treated with GDA (50 mg/kg i.p.) after which they
received either PCP (5 mg/kg i.p.) or amphetamine (5 mg/kg i.p.).
Both PCP and amphetamine induced significant levels of
hyperactivity. Pretreatment with GDA did not significantly affect
basal activity. However, GDA significantly reduced the degree of
hyperactivity induced by PCP (t=4.09, p<0.001) (FIG. 2). In
contrast, the level of hyperactivity induced by amphetamine was not
significantly altered (t=0.59, p>0.5). GDA-induced inhibition of
PCP-induced hyperactivity was significantly dose-dependent with 50
mg/kg GDA inducing a reduction of hyperactivity to below 70% of
control (PCP alone) levels, and 100 mg/kg GDA inducing a reduction
to below 50% of control (t=5.04, p<0.001) (FIG. 3).
[0032] Because it was assumed that the majority of glycineamide
derivatives tested would be less potent that GDA in reversing
PCP-induced hyperactivity, a dose of 100 mg/kg i.p. was chosen for
comparative testing. As has been reported previously (Toth et al.,
1986), glycylhexylamide (G6A) did not significantly inhibit
PCP-induced hyperactivity. Significant reductions in activity were,
however, observed following pretreatment with G10A, GDA, and G13A,
with the degree of reduction increasing with increasing length of
the carbon sidechain (FIG. 3).
[0033] The potency with which the identified glycineamide
derivatives inhibited glycine transport in vitro was analyzed using
a synaptosomal assay system. All agents tested induced significant,
dose-dependent inhibition of synaptosomal sarcosine-sensitive
glycine uptake (FIG. 4). Agents with longer side chains showed
greater potency for inhibition of glycine transport with IC50
values in the low micromolar range, whereas shorter chain
derivatives showed IC50 values in the low to mid millimolar range.
In order to compare the potency of these agents at a concentration
relevant to the dose used for behavioral testing, all agents were
re-tested for inhibitory potency at a single fixed concentration of
100 .mu.g/ml. Significant variation was seen across compounds, with
GDA, (t=18.6, p<0.0001), G13A (t=15.3, p<0.0001), G11A
(t=6.79, p<0.001) and G10A (t=4.64, p<0.01) leading to
significant inhibition of GLYT1-mediated transport, G8A having no
significant effect (t=1.37, p>0.2), and G6A leading to
significant potentiation of transport (t=4.2, p<0.01). The
potency with which the glycineamide derivatives inhibited
GLYT1-mediated synaptosomal glycine transport correlated
significantly (p<0.05) with their potency in antagonizing
PCP-induced hyperactivity (FIG. 5).
[0034] Other agents which should be useful for treating
schizophrenia through inhibition of glycine transport include other
glycylakylamides in which the alkyl group contains 3 to 30 carbon
atoms, and structures containing branched, cyclic or polycyclic
side chains.
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[0061] Variations of the invention will be apparent to the skilled
artisan.
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