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http://www.info.med.yale.edu/eph/news/aug05/ocd_symptoms.html
Gueorguieva Author on Study Showing That Medication Eases Obsessive-Compulsive Symptoms
A medication used to ease symptoms of amyotrophic lateral sclerosis, or Lou Gehrig's disease, also is helpful in treating people with treatment-resistant obsessive-compulsive disorder (OCD), according to a pilot study at Yale School of Medicine
Although the study included only 13 patients, the preliminary results are promising for persons who have found no relief using other medications and cognitive behavioral therapy, said the first author, Vladimir Coric, M.D., assistant clinical professor in the Department of Psychiatry and director of the Yale OCD clinic.
"Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties," said Coric, who will be presenting the data Friday at the Obsessive-Compulsive Foundation annual conference in San Diego.
OCD currently is treated with serotonin reuptake inhibitors, cognitive behavioral therapy and dopamine antagonists, which reduce symptoms in 40-60 percent of patients. "However, a number of patients remain dramatically symptomatic even with the combination of pharmacotherapy and cognitive behavioral therapy," Coric said.
OCD symptoms include obsessive checking, cleaning, washing, counting, hoarding, touching, tapping, ordering, arranging, rubbing, and other repetitive behaviors. Coric said treatment-resistant OCD is one of the few psychiatric indications for neurosurgical intervention. "Novel therapeutic strategies are urgently needed," he said.
Since recent neuroimaging studies suggest that individuals with OCD have abnormalities in corticostriatal glutamate function, Coric and his colleagues tested riluzole, a glutamate modulating agent, on patients with OCD. Glutamate is the most abundant excitatory neurotransmitter in the brain, but when in excess may cause neurotoxicity. Seven of the patients treated with riluzole experienced a 35 percent reduction in symptoms and five were categorized as responsive to the treatment. One patient left the study.
"The use of glutamate modulating agents, such as riluzole, may represent a novel treatment intervention for certain anxiety and mood disorders," Coric said.
Co-authors include Sarper Taskiran, M.D., Christopher Pittenger, Suzanne Wasylink, Daniel Mathalon, M.D., Gerald Valentine, John Saksa, Yu-te Wu, Ralitza Gueorguieva, Gerard Sanacora, M.D., and Robert Malison, M.D. John Krystal, M.D., was senior author.
The study was supported in part by the NARSAD Young Investigator Award, the National Institute of Alcohol Abuse and Alcoholism, and the National Institute of Health.
Recent Patents on CNS Drug Discovery, 2007, 2, 47-55 47
1574-8898/07 $100.00+.00 © 2007 Bentham Science Publishers Ltd.
Glutamatergic Dysfunction-Newer Targets for Anti-Obsessional Drugs
Sagnik Bhattacharyya1,* and Koushik Chakraborty2
1Section of Neuroimaging, Box 67, Division of Psychological Medicine, Institute of Psychiatry, King’s College London,
De Crespigny Park, SE5 8AF, UK, 2Department of Molecular Neurobiochemistry, International Graduate School of
Neuroscience. Ruhr University Bochum, Universitatsstrasse 150, 44780 Bochum, Germany
Received: September 13, 2006; Accepted: September 15, 2006; Revised: October 5, 2006
Abstract: Despite widespread use and validation of their efficacy, about 40-60% of obsessive compulsive disorder (OCD)
sufferers do not respond to appropriate courses of treatment with serotonin reuptake inhibitors (SRI) and even with the
combination of pharmacotherapy and cognitive behaviour therapy a substantial number of patients remain dramatically
symptomatic. Recently, there has been increasing interest in investigating glutamatergic dysfunction in OCD. Multiple
lines of evidence point toward glutamatergic dysfunction being related to the pathophysiology of OCD, with glutamate
modulating drugs being an alternative pharmacological strategy for treating OCD. In this article we focus in detail on the
rationale for targeting glutamatergic agents as well as review the recent important patents for compounds that have
emerged from these studies.
Keywords: Glutamate, serotonin, obsessive compulsive disorder, metabotropic glutamate receptor antagonist.
INTRODUCTION
Obsessive-compulsive disorder (OCD) is a severe and
often chronic illness, characterised by recurrent, persistent
and intrusive thoughts that cause considerable distress or
anxiety (obsessions) and repetitive ritualistic behaviours or
mental acts that are performed excessively (compulsions). It
has a lifetime prevalence of 1.9- 2.5 % across multinational
sites [1] which is about twice the lifetime prevalence rates of
schizophrenia [2]. Because of its high prevalence rates and
the disabling nature of its symptoms, OCD has been named
by the World Health Organization among the top 10 causes
of years lived with illness-related disability [3]. While the
economic and social burden of OCD is difficult to quantify,
one study estimated it to be around $8.4 billion in the United
States alone in 1990 [4].
Although a few decades ago, OCD was considered to be
almost entirely treatment-resistant, serotonin reuptake inhibitors
(SRI) are now the first line pharmacological treatment at
most centres [5]. In fact, efficacy of SRIs in OCD originally
led to the serotonergic dysfunction hypothesis of OCD,
which has now been present for over two decades [6].
However, despite widespread use and validation of their
efficacy [7,8], about 40-60% of OCD sufferers do not
respond to appropriate courses of SRI treatment [9,10] and
even with the combination of pharmacotherapy and Cognitive
Behaviour therapy a substantial number of patients
remain dramatically symptomatic [11]. Non-response to
SRIs in a substantial number of OCD patients has led to
studies investigating the role of other neurotransmitter
systems as well as pharmacological agents acting on these
neurotransmitter systems in OCD.
In this review, we discuss in detail on the rationale for
targeting glutamatergic agents as well as the recent patents
*Address correspondence to this author at the Section of Neuroimaging,
Box 67, Division of Psychological Medicine, Institute of Psychiatry, King’s
College London, De Crespigny Park, SE5 8AF, UK; Tel: +44 20 78480355;
Fax: +44 20 78480976; E-mail: s.bhattacharyya@iop.kcl.ac.uk
for glutamatergic compounds that have emerged from these
studies.
NEUROTRANSMITTER DYSFUNCTIONS IN OCD
Various neurotransmitters and neurochemicals have been
implicated in the pathophysiology of OCD. There is a growing
body of literature from imaging [12-16], cerebrospinal
fluid (CSF) [6,17,18] and pharmacological challenge stu-dies
[19] supporting the serotonergic dysfunction hypothesis in
OCD. Clinical studies [20, 21] as well as animal models of
OCD [22,23] and findings from imaging studies [13,15,24,
25] have also suggested the presence of dopaminergic
dysfunction in OCD. Researchers have examined the role of
the opioid system [26] and neuropeptides like oxytocin and
vasopressin [27,28] in OCD although the evidence has been
equivocal. Emerging evidence reviewed below has recently
implicated glutamatergic dysfunction in OCD. Although, it
is likely that the underlying pathophysiology of OCD is a
result of complex interaction between the various neurotransmitter
dysfunctions implicated in OCD, recent evidence
suggesting glutamate abnormalities in OCD have however
opened up new avenues for developing pharmacological
approaches to treating OCD.
GLUTAMATERGIC DYSFUNCTION IN OCD
Several different lines of evidence including functional,
structural, and spectroscopic brain imaging studies have
implicated dysfunction in either the ‘direct’ or ‘indirect’
loops of the cortico-striato-pallido-thalamo-cortical circuit in
OCD [29]. This circuit involves a complex neurotransmitter
network, where dopamine, serotonin, glutamate, and GABA
dysfunction have been implicated in OCD [30]. Recently,
there has been increasing interest in investigating the role of
glutamate in OCD, which is the primary excitatory neurotransmitter
[31], in the cortico-striatal-pallido-thalamocortical
circuits and is also known to interact extensively
with serotonin and dopamine [32]. Several lines of evidence
48 Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 1 Bhattacharyya and Chakraborty
summarised below have accumulated implicating dysfunction
in glutamatergic systems in OCD.
EVIDENCE FROM NEUROIMAGING STUDIES
Neuroimaging evidence implicating glutamatergic
dysfunction in OCD has come primarily from studies using
magnetic resonance spectroscopy (MRS), a method which
allows quantification of various small molecules in the brain.
In one of the first reports implicating glutamatergic dysfunction
in OCD, Moore et al. (1998) [33] reported striking
changes in caudate Glx (a marker for combined glutamate
and glutamine) resonance on proton magnetic resonance
spectroscopy (1H-MRS) in a paediatric OCD patient following
treatment with Paroxetine. Subsequently, Rosenberg et
al. (2000) [34] studied 11 psychotropic drug-naïve children
with OCD, with single-voxel 1H-MRS examinations and
demonstrated that caudate Glx concentrations were
significantly greater in the patients compared to healthy
controls. They also found that the caudate Glx levels in
patients decreased significantly following 12-weeks
treatment with Paroxetine to levels comparable to that of
controls and the decrease was associated with decrease in
symptom severity of the OCD patients, while there was no
difference in Glx levels in the occipital cortex between the
two groups. In a subsequent report, Bolton et al. (2001) [35]
reported that the decrease in left caudate Glx levels on 1HMRS
following 12 weeks treatment with Paroxetine
persisted 3 months after medication discontinuation in an 8-
year old girl, who was part of the earlier sample of
Paroxetine- treated OCD patients. In a later study from the
same group, there was however decrease in the absolute Glx
level in the anterior cingulate of children with OCD [36].
More recently, Whiteside et al. (2006) [37] have demonstrated
that within the right orbitofrontal white matter, relative
levels of Glx and N-acetylaspartate were increased in adult
patients with OCD compared with healthy controls and
greater levels of Glx/Creatine were associated with more
severe OCD symp-toms. Despite the well-known methodological
shortcomings of MRS in quantification of glutamate
levels [38, 39], the results from the above studies consistently
implicate glutamatergic dysfunction in OCD. Although
it is unknown whether Glx concentrations are a marker
of brain activity, Glx has been found to have a direct relation
to brain metabolism as measured by Positron emission
tomography [40]. Interestingly, if Glx is considered to
represent brain activity, evidence of Glx changes as observed
using MRS are also consistent with evidence from other
imaging studies suggesting hyperactivity in the corticostriato-
thalamo-cortical circuit or increased cortical excitability
in OCD [41, 42]. Thus emerging evidence from neuroimaging
studies are generally consistent in implicating
glutamatergic dysfunction in OCD.
EVIDENCE FROM GENETIC STUDIES
Although, a number of family studies have established
significant familial aggregation in OCD, there has not been
much success in identifying candidate genes in OCD [43-
45]. Until recently, results from the few genetic studies that
have investigated glutamate-related candidate genes in OCD,
have been mixed. Hanna et al. (2002) [46] published a
genome scan based on OCD probands where they found a
region suggestive of linkage (LOD score-2.25) in chromosome
9p which contains the neuronal glutamate transporter
gene SLC1A1, though there was no evidence for biased
transmission in OCD families. Subsequently, Arnold and
colleagues (2004) [47] demonstrated a significant association
between a polymorphism in the 3´ untranslated region of
GRIN2B (glutamate receptor, ionotropic, N-methyl-Daspartate
2B) and OCD after correction for multiple testing,
though another group did not find any association between
OCD and two of the kainate subtype of glutamate receptors,
GRIK2 (glutamate receptor ionotropic kainate 2) and GRIK3
(glutamate receptor ionotropic kainate 3) [48]. To put this in
perspective, it is worth noting that although genes related to
the serotonergic and dopaminergic system have been
intensively investigated in OCD, no genetic association has
been identified [49].
However, recently two independent groups of investigators
have reported statistically significant association
between OCD and a locus on chromosome 9p24 that codes
for a high-affinity neuronal/epithelial excitatory amino acid
transporter (EAAC-1), also known as SLC1A1 (Solute
carrier family 1, member 1) [50,51]. It is thought that in the
brain this transporter is crucial in terminating the action of
the excitatory neurotransmitter glutamate and in maintaining
extracellular glutamate concentrations within a normal range
[52]. Although not conclusive, evidence from genetic studies
add to the growing body of evidence implicating glutamatergic
abnormalities in OCD.
EVIDENCE FROM ANIMAL MODELS
Further evidence implicating glutamatergic transmission
in OCD has come from studies with animal models of OCD.
McGrath et al. (2000) [53] demonstrated using the D1CT
transgenic mice model of comorbid Tourette’s syndrome and
OCD (TS+OCD) [23], that glutamatergic drugs such as MK-
801, a non-competitive NMDA receptor antagonist,
indirectly stimulate the cortical-limbic glutamate output and
aggravate a transgene-dependent abnormal behaviour (repetitive
climbing and leaping) in the D1CT transgenic mice [a
transgenic mouse model expressing the neuropotentiating
cholera toxin (CT) transgene in a subset of dopamine D1
receptor expressing neurons]. In order to determine the
glutamate receptor type involved in the process the authors
used NBQX, a seizure-inhibiting AMPA receptor antagonist,
which only reduced the MK-801 dependent stereotypic and
limbic seizure behaviour of the D1CT mice, but not their
transgene-dependent behaviours. The authors concluded that
their data strongly suggested that TS+OCD like behaviours
are mediated by cortical-limbic glutamate dysfunction,
where AMPA glutamate receptors may not play an essential
part in the behavioural circuitry. They went on to predict that
drugs acting on metabotropic glutamate subtype 2-3
receptors that attenuate glutamatergic output from the
cortical-limbic regions may be beneficial in treating OCD.
Further evidence supporting a glutamatergic dysfunction in
OCD came from another study in which transgenic mice
with increased glutamate output to the striatum exhibited a
phenotype similar to comorbid OCD and Tourette syndrome
including generalized behavioural perseveration, compulsive
leaping, grooming-associated pulling and biting of skin and
hair (similar to trichotillomania), and tics [54].
Glutamatergic Targets for OCD Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 1 49
EVIDENCE FROM PHARMACOLOGICAL STUDIES
Evidence has also been accumulating in recent years of
the effectiveness of glutamate-modulating agents in the
treatment of OCD. Poyurovsky et al. (2005) [55] used
Memantine, an N-methyl-D-aspartic acid (NMDA) glutamatergic
receptor antagonist, in treating a case of treatmentresistant
OCD and demonstrated its therapeutic effect. The
study suggested that Memantine was well tolerated and
resulted in clinically significant reduction of the OCD
symptom severity. Lafleur et al. (2006) [56] also published a
case report of the beneficial effect of N- acetylcysteine, an
amino acid derivative, in a female OCD patient, who had not
responded to two previous trials of SRIs (Fluoxetine and
Clomipramine) and only partially responded to a trial with a
third SRI (Fluvoxamine). There was more than 20 point
reduction in OCD symptom severity ratings following Nacetylcysteine
augmentation of Fluvoxamine over a 12-week
period of combined treatment, which persisted during
follow-up 2 months later. The authors hypothesized that the
benefits associated with N-acetylcysteine in this patient was
related to its ability to reduce synaptic glutamatergic activity
perhaps via activation of group II metabotropic glutamate
receptors. There have been other studies investigating the
beneficial effect of Morphine (in a double-blind trial) [57]
and Tramadol hydrochloride, an opiate agonist (in a openlabel
study) [58] in treatment-resistant OCD. Koran et al.
(2005) [57] concluded that while mu-opioid receptor
mediated disinhibition of midbrain serotonergic neurons
could explain the beneficial effect of mu-receptor agonists
like morphine in OCD, an alternative explanation was mureceptor
mediated blockade of serotonin-induced release of
excitatory neurotransmitter glutamate in the medial
prefrontal cortex and other areas of brain.
The most promising glutamate-modulating agent investigated
thus far in treating OCD has been Riluzole (2-amino-
6-trifluro methoxy-benzthiazole) [Fig. (1)], a Na+ channel
blocker exhibiting potent anti-glutamatergic properties.
Riluzole is a neuroprotective agent that inhibits the release of
glutamate from nerve terminals, inactivates voltage-
Fig. (1). Riluzole.
dependent sodium channels in cortical neurons and blocks
GABA uptake [59, 60]. It modulates both kainate and
NMDA receptors and inhibits excitotoxic injury in
experimental models of cerebral ischemia, Parkinson’s
disease and Amyotrophic lateral sclerosis (ALS) and has
been demonstrated to be neuroprotective in glutamateinduced
excitotoxic cell death in vitro as well as in vivo [61,
62]. In an open label study, Riluzole was associated with
significant antidepressant effects in patients with bipolar
depression [63]. In a similar study, authors found Riluzole to
be an effective medication for patients with generalized
anxiety disorder [64]. A recent open label study demonstrated
anti-obsessional effects of Riluzole in treatmentresistant
OCD, which the authors concluded was related to
attenuation of glutamatergic activity [65]. The authors
suggested that further studies would be required to determine
whether Riluzole preferentially targets components of the
cortico-striato-thalamic circuitry or has a more global effect.
Interestingly, a recent study showed the ability of Riluzole in
reversing behavioural deficits induced by excitotoxic
prefrontal cortex lesion, where the authors hypothesized that
the mechanism through which Riluzole bestowed neuroprotection
may involve various pathways including an inactivation
of voltage-dependent sodium channels, inhibition of
excitatory amino acid release through a G-protein signalling
pathway and possibly, a blockade of NMDA receptors [66].
EVIDENCE FROM CSF STUDIES
More recently, in the only published study investigating
CSF glutamate levels in OCD Chakrabarty et al. (2005) [67]
found CSF glutamate levels in psychotropic drug-naïve OCD
patients to be significantly higher compared to psychiatrically
normal controls, further implicating glutamatergic
excess in the pathophysiology of OCD. While the authors
did not find any relationship between OCD symptom
severity and CSF glutamate levels, they opined that this was
possibly because there is a complex interplay between
various neurotransmitter dysfunctions rather than centrality
of one neurotransmitter dysfunction in OCD, ruling out any
simple correlation between OCD symptom severity scores
and CSF glutamate levels. The authors also noted that
though increased CSF glutamate is not the same as increased
glutamatergic activity in the cortical and subcortical pathways,
it is worth noting that various studies have demonstrated
the existence of a blood-CSF barrier to amino acids
and suggested that CSF glutamate concentrations should
reflect its function within central nervous system.
Available evidence reviewed thus far strongly implicates
a role for glutamatergic dysfunction in OCD. Although not
entirely clear, it is likely that this dysfunction is characterised
by glutamatergic hyperactivity which leads to hyperactivity
of the OCD circuit in the cortico-striato-pallidothalamo-
cortical pathways. Attempts at reducing this
hyperactivity by targeting glutamatergic receptors with
pharmacological agents thus may prove beneficial as an
alternative therapeutic strategy in OCD. However, because
of the widespread distribution of glutamatergic receptors and
glutamatergic neurotransmission, any such attempts need to
carefully target receptors that specifically have an impact on
pathways relevant to OCD. We shall now review briefly the
pharmacology of glutamate and its receptors and evidence
suggesting any potential targets for treatment in OCD.
GLUTAMATE AND ITS RECEPTORS- MOLECULAR
TARGETS FOR ANTIOBSESSIONAL AGENTS
Glutamate is the major excitatory neurotransmitter in the
brain and glutamatergic neurotransmission is mediated
through and regulated by various receptors and transporters.
They include the two different groups of receptors [68],
Ionotropic (iGluR) receptors [including N-methyl-D-aspartate
(NMDA), a-amino-3 hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) and Kainate subtypes] which are ion
channels permeable to cations and directly mediate synaptic
excitability and plasticity and Metabotropic (mGluR)
receptors, which are G protein coupled and regulate
S
N
H2N
O
F
F
F
50 Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 1 Bhattacharyya and Chakraborty
glutamate release and postsynaptic excitability to glutamate.
The mGluRs are classified into three groups based on sequence
homology, second messenger coupling and pharmacological
characteristics [69]. They include Group I mGluRs
(mGluR1 and mGluR5) which are coupled to phospolipase
C, Group II mGluRs (mGluR2 and mGluR3) and Group III
mGluRs (mGluR 4, mGluR6, mGluR7 and mGluR8) both of
which are negatively coupled to adenylyl cyclase. In
addition, there are plasma membrane glutamate transporters,
which clear released glutamate from the synaptic space
[Excitatory amino acid transporters (EAAT) (1-5) and
Vesicular glutamate transporters (vGluT1 and vGluT2)
involved in excytotic glutamate release]. Although, pharmacological
agents that modulate glutamatergic transmission by
acting on ionotropic receptors have been investigated in the
context of treatment of anxiety [70], their propensity to
produce problematic side-effects, owing to ubiquitous
expression of their target receptors, have prevented their
clinical application in the treatment of anxiety disorders [71-
73]. This has led to the idea that pharmacological agents that
more selectively target glutamatergic system and suppress
glutamate hyperexcitability might be better tolerated and
more efficacious in treatment of anxiety [73]. Consequently
the focus has shifted to metabotropic glutamate receptors as
targets for development of anxiolytic drugs. Though
receptors belonging to each of the groups of metabotropic
glutamate receptors may be located both pre- and postsynaptically,
Group I mGluRs (mGluR1 & mGluR5) are
typically located post-synaptically from where they regulate
neuronal excitability, while Group II mGluRs (mGluR 2 &
mGluR 3) and most of Group III mGluRs (mGluR4,
mGluR7, mGluR8) except mGluR6 are typically located
presynaptically and are involved in the regulation of release
of Glutamate or other neurotransmitters [74]. Although all
three groups of mGluRs have been shown to be able to
modulate glutamatergic transmission, for the purposes of this
review, we shall focus on pharmacological agents acting on
Group I and II mGluRs, as there are few pharmacological
agents with the properties and receptor type selectivity ideal
for testing the significance of the subtypes of Group III
mGluRs in anxiety [73]. Interestingly, the different subtypes
of Group I and II mGluRs have also been localized to areas
hypothesized to be hyperactive in OCD [29]. Both mGluR1
and mGluR5 have been shown to be expressed in neocortical
and limbic cortical regions, basal ganglia and
thalamus [74]. Similarly, Group II mGluRs have also been
shown to be expressed extensively in the striatum, neocortex
and various limbic cortical regions, with moderate expression
in the thalamus [74]. Activation of Group I mGluRs
leads to increase in cell excitability through potentiation of
NMDA responses [75]. Thus, one would expect mGluR1 and
mGluR5 antagonists to normalize the increase in glutamatergic
activity in areas of the brain implicated in OCD. On
the other hand, activation of Group II mGluRs, which are
typically located presynaptically, causes reduction in
glutamatergic activity [75]. Although one would expect then
that mGluR2 and mGluR3 agonists would be potential
therapeutic targets in OCD, as in many other anxiety
disorders [73], it is interesting to note that available evidence
as discussed below [76], suggests beneficial effect of
antagonists at Group II mGluRs in animal models of OCD.
One of the earliest evidence suggesting potential beneficial
effect of pharmacological agents acting at metabotropic
glutamate receptors in OCD came from Spooren et al. (2000)
[77], who examined the effect of the prototype metabotropic
glutamate receptor 5 antagonist MPEP (2-methyl-6-phenylethynylpyridine)
[Fig. (2)] in animal models of anxiety.
MPEP was noted to have a significant effect in the marble
burying test, a well-known animal model of OCD [78], in
addition to its effect on various other animal models of
anxiety.
Fig. (2). MPEP.
More recently, Shimazaki et al. (2004) [76] demonstrated
that MGS0039 [(1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-
6-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic
acid] [Fig. (3)] and LY341495 (2S,1´S, 2´S)-2-(9-xanthylmethyl)-
2-(2´-carboxycycloprolyl) glycine] [Fig. (4)], which
are group II metabotropic glutamate (mGlu) receptor antagonists,
inhibited marble-burying behaviour and that this
effect was significantly attenuated by a group II mGlu
receptor agonist.
Fig. (3). MGS0039.
Fig. (4). LY341495.
Although, numerous pharmacological agents acting at the
different groups of metabotropic glutamate receptors have
been investigated for their beneficial effect on anxiety
disorders in general (reviewed by Swanson et al., 2005) [73],
the available evidence from preclinical studies supporting
their potential therapeutic effect specifically in OCD is
limited at best. However, the limited available evidence [76,
77] coupled with current understanding about a hyperactive
glutamatergic system, at least in some areas of the brain,
being related to the pathophysiology of OCD, suggests a
potential therapeutic role for antagonists at Group I and
Cl
Cl
O NH2 HOOC
H
COOH
H F
N
O
HOOC
H
H2N COOH
Glutamatergic Targets for OCD Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 1 51
Table1. List of Patents of Group I and II Metabotropic Glutamate Receptor Antagonists
Number of
compound
Chemical Structure Biological
data
Patent number Name of
Company
Reference
Number
1.
Polyheterocyclic compounds
IC50- 199
nM
WO05080386A1
(2005)
AstraZeneca
AB and NPS
Pharmaceutic
als Inc.
79
2
Fused heterocyclic compounds
WO05080397A2
(2005)
AstraZeneca
AB and NPS
Pharmaceutic
als Inc.
80
3.
Formula 1
Formula 2
Triazole compounds
IC50- 265
nM
WO05080379A1
(2005)
AstraZeneca
AB and NPS
Pharmaceutic
als Inc.
81
4.
Acetylinic piperazine compounds
Example: 4-Prop-2-ynyl-piperazine-1-
carboxylic acid ethyl ester
WO05080363A1
(2005)
AstraZeneca
AB and NPS
Pharmaceutic
als Inc.
82
5.
Additional heteropolycyclic compounds
Example: 2-[5-(3-Methoxy-Phenyl)-[1,2,4]
Oxadiazol-3-ylmethylsulfanyl]-1H-Benzoimidazole
US20050272779A1
(2005)
AstraZeneca
AB and NPS
Pharmaceutic
als Inc.
83
X6
X5
X1
2
X3 X4
Q
P
X
(R2)n
(R3)p
(R1)m
X7
X2 X3
X8
X1
X4
P
Q
(R1)m (R2)n
(R3)p
R1
R2
X1
X5 X4
X3
X2
X6
X9
X8
X10
X7 XG
R1
(R4)n
N
X2 X3
X1
X4
R3
X6
X5 N P
(R1)m
(R2)n
R1
R2
M N N R3
(R4) n
X1
X2 XM 3 1
M2
X4
(R1)m P Q
(R2)n
(R3)n
(R4)m
52 Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 1 Bhattacharyya and Chakraborty
Table 1 Contd….
Number of
compound
Chemical Structure Biological
data
Patent number Name of
Company
Reference
Number
6.
Formula I
Example: 3-(2-pyridyl)-5-(3-methoxyphenyl)-
1,2,4-oxadiazole
Formula II
Example: 4-(3-Cyanophenyl)-1-(2-pyridyl)-
1H-imidazole
IC50- 11-
9140 nM
US20050154027A1
(2005)
NPS
Pharmaceutic
als Inc.
84
7.
Example: 3-(7-Iodo-4-oxo-4,5-dihydro-3Hbenzo[
B][1,4]diazepin-2-yl)-benzonitrile
US6960578 (2005)
Hoffmann-La
Roche Inc.
86
8
Example: 3-(4-Oxo-7-phenylethynyl-4,5-
dihydro-3H-benzo[b][1,4]diazepin-2-yl)-
benzonitrile
US2005234048 A1
(2005)
Hoffmann-La
Roche Inc.
87
9.
Formula I
Formula II
US20050209273A1
(2005)
Janssen
Pharmaceutic
a N.V.
88
Group II metabotropic glutamatergic receptors in OCD. We
review below some of the recent patents that have been
published in this area. Most of the patents reviewed below
describe compounds that are specifically active at Group I
mGluRs.
PATENTS
Several patent applications and/ or registrations have
been published especially over the last year presenting
metabotropic glutamate receptor antagonists. Table 1 lists
most of the recent patents that have been published on Group
Y
Ar1 X Ar2
Z
Y2
X2
Ar1 Ar1
N
HN
O
R3
X
R1
N
HN
O
R3
X
R1
N
R4
R3
R2
R5
X
R1 C
N
R4
R3
R2
X
R1 C
Glutamatergic Targets for OCD Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 1 53
I and II metabotropic glutamate receptor anatagonists,
showing some of the examples of the specific inventions. A
number of patent applications have been published by
AstraZeneca AB and NPS Pharmaceuticals Inc, which
includes either polyheterocyclic, fused heterocyclic, triazole
or acetylinic piperazine compounds which act as antagonist
at metabotropic glutamate receptors especially at mGluR5
receptor [79-82] (Table 1). According to the patents, these
compounds are expected to be useful in the treatment of
conditions associated with excitatory activation of mGluR5
receptor and for inhibiting neuronal damage caused by
excitatory activation of mGluR5. AstraZeneca AB and NPS
Pharmaceuticals Inc have published another patent presenting
additional heteropolycyclic compounds which exhibit a
high degree of potency and selectivity for individual
metabotropic glutamate receptor (mGluR) subtypes [83]
(Table 1). The patent describes that in particular there are
compounds that are potent and selective for the mGluR
Group I receptor and more particularly for mGluR5.
Accordingly, the compounds of the invention were expected
to be useful in the prevention and/or treatment of conditions
associated with excitatory activation of an mGluR Group I
receptor and for inhibiting neuronal damage caused by
excitatory activation of an mGluR Group I receptor,
specifically when the mGluR Group I receptor is mGluR5.
NPS Pharmaceuticals Inc have published another patent
presenting heterpolycyclic compounds that are potent and
selective antagonists for mGluR5 [84]. F. Hoffmann-La
Roche. Inc. has published a patent for phenylethenyl and
phenylethinyl derivatives as glutamate receptor antagonists
which they applied for in Slovenia and for which they have
applied for multiple patents in USA [85]. F. Hoffmann-La
Roche Inc has also published two more patents for new
Benzodiazepine derivatives which are Group II metabotropic
glutamate receptor antagonists [86, 87] (Table 1). Janssen
Pharmaceutica N.V. has also published a patent for new
quinoline or quinolinone derivatives which are metabotropic
glutamate receptor antagonists [88].
Earlier, especially over 2003 and 2004 several other
patent applications have been published by various
companies including Merck, F. Hoffmann-La Roche AG,
Euro-celtique, AstraZenca, Addex Pharmaceuticals and
Novartis, presenting mGluR5 antagonists which have been
well summarised in a review by Chaki et al. (2005) [89].
F. Hoffmann-La Roche has also published patents for
mGluR2 antagonists as reviewed by Chaki et al. (2006) [89].
CURRENT & FUTURE DEVELOPMENTS
Multiple lines of evidence as summarised above point
towards glutamatergic dysfunction, more specifically
glutamatergic hyperactivity, as being related to the
pathophysiology of OCD. Thus, pharmacological approaches
to modulate glutamatergic activity are likely to be beneficial
in the treatment of OCD. Metabotropic glutamate receptor
antagonists, especially because of their distribution in the
central nervous system as well as their ability to modulate
and stabilize glutamatergic hyperactivity, appear to be the
most likely targets in this approach. Preclinical evidence
provides support in favour of this approach to treating OCD.
While metabotropic glutamatergic antagonists may have
potential therapeutic applications, other pharmacologic
agents acting at metabotropic glutamatergic receptors also
may have important application as pharmacological probes
in imaging studies of OCD and other anxiety disorders as
well as depressive disorders in addition to development of
pharmacological models of OCD and other anxiety
disorders. Further preclinical research investigating pharmacological
agents that are more specific agonists or antagonists
at the various subtypes of metabotropic glutamate
receptors is warranted, while clinical research needs to
establish the efficacy and tolerability of the already characterised
promising metabotropic glutamate receptor
antagonists in OCD.
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http://info.med.yale.edu/psych/clinics/OCD%20Research%20Clinic/glutamate%20levels.htm
Yale OCD Research Clinic
Cerebral glutamate levels in OCD: pathophysiology and predictors of response
HIC: pending
A number of studies using different techniques have suggested that the neurotransmitter glutamate is present at excessive levels in at least some patients with OCD. This idea has motivated our use of glutamate-modulating drugs in OCD that has not responded to standard therapies. However, the details of how glutamate is out of balance in OCD remain unclear. Likewise, it is unclear whether glutamate dysregulation contributes to all forms of OCD or only to some subtypes. Better understanding this issue may, in the future, help us select which therapies are most likely to work for individual patients.
We use an imaging method, magnetic resonance spectroscopy (MRS), that allows us to measure the levels of glutamate and related molecules in the brain. This is done in a brain scanner very similar to that used for the MRI imaging that is standard in all hospitals. By better understanding how and where glutamate is disrupted in OCD, we hope to expand our knowledge of the biological changes that contribute to the disorder and how to develop new medication strategies to address them.
Last modified: February 11, 2008
http://www.med.umich.edu/opm/newspage/2006/ocd.htm
July 26, 2006
New genetic findings add to understanding of obsessive-compulsive disorder
Studies of DNA from OCD patients and their relatives lead U-M, Chicago and Toronto teams to find consistent genetic association
ANN ARBOR, MI – Obsessive-compulsive disorder tends to run in families, causing members of several generations to experience severe anxiety and disturbing thoughts that they ease by repeating certain behaviors. In fact, close relatives of people with OCD are up to nine times more likely to develop OCD themselves.
Now, new research is shedding new light on one of the genetic factors that may contribute to that pattern. And while no one gene “causes” OCD, the research is helping scientists confirm the importance of a particular gene that has been suspected to play a major role in OCD’s development.
In two papers published simultaneously in the Archives of General Psychiatry, researchers from the University of Michigan, the University of Illinois at Chicago (UIC), the University of Chicago and the University of Toronto report finding an association between OCD patients and a glutamate transporter gene called SLC1A1.
The gene encodes a protein called EAAC1 that regulates the flow of a substance called glutamate in and out of brain cells. So, variations in the gene might lead to alterations in that flow, perhaps putting a person at increased risk of developing OCD.
The new findings are especially important not only because of the simultaneous discoveries reported in the papers, but also because of previous studies that show a functional link between glutamate and OCD. Brain imaging and spinal fluid studies have shown differences in the glutamate system between OCD patients and healthy volunteers, including in areas of the brain where the EAAC1 protein is most common.
“Taken together, these findings suggest that SLC1A1 is a strong candidate gene for OCD, which if confirmed could lead to improvements in understanding and treating this condition, and screening those with an elevated risk,” says Gregory Hanna, M.D., senior author on one of the papers and an associate professor of psychiatry at the U-M Medical School. “It’s possible that altered glutamate activity in some brain regions may contribute to the obsessions and compulsions that are the hallmark of OCD.”
Hanna and colleague Edwin Cook, Jr., M.D., of UIC together lead a major study of OCD genetics involving patients and their families who are willing to donate DNA samples and be interviewed by researchers. The study is still seeking OCD patients and their parents to participate in further research on the genetics of OCD.
While the new findings are exciting because they strengthen the evidence for glutamate’s role in OCD vulnerability, the researchers caution that more work needs to be done before their discovery has any impact on OCD treatment.
Four years ago, the U-M and UIC team published a genome scan from young OCD patients and their parents that found signs of OCD-related genetic variations on chromosome 9, in the area of SLC1A1.
Since that time, they have been zeroing in on the gene and its nearby stretches of DNA, using analyses of single nucleotide polymorphisms that look at specific differences between individuals within the gene. At the same time, the Toronto group has been focusing on that same area in studies involving adults and children with OCD and their close relatives.
The new U-M, UC and UIC paper is based on genetic samples from 71 OCD patients (children and adults) and their parents. It finds a significant association between early-onset OCD and genetic variations at several sites on the SLC1A1 gene. A strong association at two of those sites was only seen in male early-onset OCD patients, which surprised the researchers but may make sense in light of the fact that early-onset OCD is more common in boys than in girls. As many as half of all OCD patients experience their first symptoms in childhood or adolescence.
The new U-T paper is based on data from 157 OCD patients and 319 of their first-degree relatives. It finds linkages between OCD and three locations on the SLC1A1 gene. |
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