| Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 8, Number 5, May 2007
Contents
Glutamate Receptors and Related Processes as Drug Targets
Guest Editor: Michel Baudry
Editorial Pp. 571-572
Structure of Glutamate Receptors Pp.
573-582
R.E. Oswald, A. Ahmed, M.K. Fenwick and A.P. Loh
[Abstract]
Pharmacology of Ampakine Modulators: From AMPA Receptors
to Synapses and Behavior Pp. 583-602
A.C. Arai and M. Kessler
[Abstract]
AMPA Receptor Potentiators: Application for Depression
and Parkinson’s Disease Pp. 603-620
M.J. O’Neill and J.M. Witkin
[Abstract]
Pathologically-Activated Therapeutics for Neuroprotection:
Mechanism of NMDA Receptor Block by Memantine and S Nitrosylation
Pp. 621-632
S.A. Lipton
[Abstract]
The Molecular Basis of Conantokin Antagonism of NMDA
Receptor Function Pp. 633-642
M. Prorok and F.J. Castellino
[Abstract]
Glycine Transporter 1 Inhibitors and Modulation of
NMDA Receptor-Mediated Excitatory Neurotransmission
Pp. 643-649
C. Sur and G.G. Kinney
[Abstract]
Metabotropic Glutamate Receptors as Drug Targets
Pp. 651-681
M. Récasens, J. Guiramand, R. Aimar, A. Abdulkarim
and G. Barbanel
[Abstract]
Abstracts
[Back to top]
Editorial
Glutamate is the major excitatory neurotransmitter in
the brain. Surprisingly, only recently have glutamate receptors
become important targets for drugs designed to address a large
variety of neurological and neuropsychiatric diseases. The
multiplicity of glutamate receptors, both ionotropic and metabotropic,
and the large variety of functions in which they are involved,
have therefore provided a rich field of application for the
discovery of new therapeutic approaches. In particular, glutamate
receptors have been shown to play critical roles in the mechanisms
underlying learning and memory, and numerous academic laboratories
and pharmaceutical companies have evaluated the possibility
of developing cognitive enhancers based on positive modulation
of AMPA receptors. Conversely, it is also clear that AMPA
receptors are implicated in epilepsy and numerous AMPA receptor
antagonists are in various phases of development as anti-epileptic
agents. NMDA receptors have also been the targets of drug
companies. The recent approval of memantine for treatment
of Azheimer’s disease represents an interesting example
of bench to bedside transition. On the other hand, modulators
of the glycine site of the NMDA receptors as well as glycine
uptake inhibitors have been shown to provide a positive complement
to the traditional use of neuroleptics to manage schizophrenia.
Finally, agents acting on the metabotropic glutamate receptors
are also slowly making their way to the clinic. This Special
Issue of Current Drug Targets will review several recent developments
in both the basic sciences directed at further understand
the structures and functions of the different subtypes of
receptors as well as the applications of the research directed
at developing new therapeutic treatments for a variety of
CNS diseases.
Since the cloning of the glutamate receptors in the early
90s, tremendous progress concerning the structures and functions
of the different subtypes of glutamate receptors has been
accomplished. This progress has led to a flurry of activities
directed at the identification of molecules targeting various
aspects of the receptors and receptor-related processes, i.e.,
modulators of the receptor themselves or of mechanisms related
to transport of endogenous regulators of receptor function
such as glycine, which could be useful for a variety of therapeutic
indications (Fig. 1). Given the fact that
glutamate is the major excitatory neurotransmitter, it is
not surprising that modulating glutamate receptor functions
could produce a wide range of physiological effects, and that
pharmaceutical as well as biotech companies would be interested
in targeting these receptors for therapeutic applications.
Fig. (1). Schematic drawing of a
glutamatergic synapses and the various targets discussed in
the different chapters.
The first contribution by Robert Oswald and colleagues focuses
on the structure of the ionotropic glutamate receptors, and
in particular on the role of the binding domain in receptor
activation. It is now clear that ionotropic receptors have
evolved from some ancestor bacterial proteins, and a lot of
information is now available regarding the 3-dimensional structure
of the binding domain of both AMPA and NMDA receptors. This
information has also been extended to additional regulatory
domains of the receptors. In particular, the N-terminal, the
C-terminal domains and the interface between dimers are now
better understood. Of primary importance is the elucidation
of the channel activation resulting from glutamate binding
to the ligand recognition domain of the receptor. Furthermore,
these studies have provided important clues for the understanding
of the mechanisms of action of compounds known as positive
AMPA receptor modulators (PARMs) that are the subjects of
the reviews by Arai and Kessler and O’Neill and Witkin.
The second contribution by Arai and Kessler describes the
structure and function of one particular class of PARMs, referred
to as Ampakines. These molecules were derived from aniracetam
and the authors discuss the evidence indicating that the various
analogs that have been synthesized belong to 2 types of compounds,
which appear to bind to 2 separate sites on the AMPA receptors
and have slightly different physiological effects. These compounds
have been shown to facilitate LTP induction and to improve
learning in a variety of experimental tasks in laboratory
animals as well as in humans. As also discussed in the following
review, these drugs exhibit neuroprotective effects presumably
through the increased expression of BDNF in various brain
structures. Interestingly, one of these drugs, CX717, was
recently reported to have beneficial effects in a Phase II
study for Attention Deficit Hyperactive Disorder (ADHD) (see
http://biz.yahoo.com/bw/060306/20060306005307.html?.v=1).
The next contribution by O’Neill and Witkin focuses
on a different class of PARMs, the barrylpropylsulphonamides,
and their potential applications for the treatment of depression
and Parkinson’s disease. In both cases, the postulated
beneficial effects of these molecules in animal models for
these diseases appear to be due to the ability of these compounds
to increase the expression and to simulate the release of
BDNF. The review discusses in details the arguments supporting
a critical role for BNDF in the etiology of depression and
summarizes the data supporting the antidepressant effects
of PARMs. The authors also review in details the various treatments
currently used or developed for Parkinson’s disease,
and make the point that the potential use of PARMs for this
disease is a logical extension of the current treatments with
a variety of growth or trophic factors. They also summarize
the data obtained with PARMs in animal models of Parkinson’s
disease. Their conclusion is that this new category of drugs
might have widespread applications for treating diseases with
various origins but associated with hypo-functioning of glutamate
receptors as well as those associated with neurodegeneration.
The following contribution by Stuart Lipton is a beautiful
example of the discovery of a drug with an unusual mechanism
of action. The author reviews the studies that have led to
the development and approval by the FDA of the use of memantine
for the treatment of Alzheimer’s disease. What is unusual
about memantine is that it is an antagonist of NMDA receptors,
and thus, it is at first thought quite surprising that it
would be beneficial for Alzheimer’s disease considering
the well-known role of NMDA receptors in learning and memory.
The key is that memantine acts as an uncompetitive, low affinity,
open channel blocker, and that it acts preferentially when
the receptors are overactivated, but not at low levels of
activity. Thus, memantine can be neuroprotective while having
minimal effect on synaptic plasticity.
This review is followed by a contrasting description of another
class of antagonists of the NMDA receptors. Mary Prorok and
Francis Castellino summarizes a wealth of data regarding the
channel blocking properties of a group of peptides found in
the venom of marine cone snails, and thus referred to as conopeptides.
One group of these peptides, the conantokins, preferentially
block NMDA receptors and have thus potential applications
in neurodegenerative diseases. In particular, conantokin-G
has a further preference for the NR2B subunit-containing NMDA
receptors, which is particularly interesting in view of recent
reports indicating that this receptor is involved in excitotoxicity.
As pointed out by the authors, these molecules might provide
some very interesting starting points in designing peptidomimetics
that could be selective for particular subtypes of NMDA receptors.
Cyrille Sur and Gene Kenney review a completely different
approach to address the problem of hypo-functioning of glutamatergic
systems that has been postulated to be involved in schizophrenia.
As NMDA receptor function requires glycine as a co-agonist,
one way to increase NMDA receptor function is to increase
extracellular levels of glycine, an amino acid that is relatively
abundant in the extracellular fluid, but whose levels are
regulated by re-uptake into glia as well as neurons (see Fig.
1). These authors describe the experimental
as well as the clinical studies that have been performed with
blockers of a particular glycine transporter designed as GlyT1,
which validate the assumption that this type of approach might
indeed be well-adapted to disease states associated with hypo-functioning
of the glutamatergic synapses.
Finally, Max Recasens and his colleagues provide a very extensive
review of the classification and functions of the glutamate
metabotropic receptors, a class of G-protein coupled receptors,
which modulate excitatory synaptic transmission by acting
both pre- and post-synaptically (Fig. 1).
They also focus on studies reporting the identification of
molecules acting as agonists, antagonists or allosteric modulators
of these different receptors. They conclude that these receptors
are likely therapeutic targets for improving numerous physiological
functions and for the treatment of different neurodegenerative
and neuropsychiatric disorders, which are related to malfunction
of glutamate signaling.
Overall, this Special Issue provides a timely review of currently
developed drugs targeting various aspects of glutamatergic
transmission. Furthermore, it indicates that there are many
new potential targets that deserve to be further studied both
at the basic and clinical levels.
Michel Baudry
Neuroscience Program
University of Southern California
Los Angeles, CA 90089-2520
USA
E-mail: Baudry@usc.edu
[Back to top]
Structure of Glutamate Receptors
R.E. Oswald, A. Ahmed, M.K. Fenwick and A.P. Loh
Glutamate receptors mediate a vast array of processes in plants,
animals and bacteria. In particular, the ionotropic glutamate
receptors (iGluRs) are the most abundant excitatory neurotransmitter
receptors in the mammalian central nervous system. Because
these proteins are constructed from distinct folding domains,
most of which can be traced to bacterial precursors, the analyses
of these important receptor proteins has been performed on
a variety of levels ranging from atomic structure and dynamics
to behavioral studies. This review will focus on the structure
and dynamics of iGluRs, with particular emphasis on the role
that the glutamate-binding domain (S1S2) plays in receptor
function.
[Back to top]
Pharmacology of Ampakine Modulators: From AMPA Receptors
to Synapses and Behavior
A.C. Arai and M. Kessler
Ampakines are drugs structurally derived from aniracetam that
potentiate currents mediated by AMPA type glutamate receptors.
These drugs slow deactivation and attenuate desensitization
of AMPA receptor currents, increase synaptic responses and
enhance long-term potentiation. This review focuses mainly
on recent physiological studies and on evidence for two distinct
subfamilies. Type I compounds like CX546 are very effective
in prolonging synaptic responses while type II compounds like
CX516 mainly increase response amplitude. Type I and II drugs
do not compete in binding assays and thus presumably act through
separate sites. Their differences are likely to have consequences
also for synaptic plasticity and behavior. Thus, while all
ampakines facilitated long-term potentiation, only CX546 enhanced
long-term depression. Further discussed are studies showing
that ampakine effects vary substantially between neurons,
with increases in EPSCs being larger in CA1 pyramidal cells
than in thalamus and in hippocampal interneurons. In behavioral
tests, ampakines facilitate learning in many paradigms including
odor discrimination, spatial mazes, and conditioning, and
they improved short-term memory in a non-matching-to-sample
task. Positive results were also obtained in various psychological
tests with human subjects. The drugs were effective in correcting
behaviors in various animal models of schizophrenia and depression.
Lastly, evidence is discussed that ampakines have few adverse
effects at therapeutically relevant concentrations and that
they protect neurons against neurotoxic insults, in part by
mobilizing growth factors like BDNF. Type II drugs like CX516
in particular appear to be inherently safe since their ability
to prolong responses is kinetically limited.
[Back to top]
AMPA Receptor Potentiators: Application for Depression
and Parkinson’s Disease
M.J. O’Neill and J.M. Witkin
α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic
acid (AMPA) receptors mediate most of the excitatory neurotransmission
and play a key role in synaptic plasticity in the mammalian
central nervous system (CNS). In recent years several classes
of AMPA receptor potentiators have been reported in the literature,
including pyrrolidones (piracetam, aniracetam), benzothiazides
(cyclothiazide), benzylpiperidines (CX-516, CX-546) and biarylpropylsulfonamides
(LY392098, LY404187, LY450108, LY451395 and LY503430). Clinical
and preclinical data have suggested that positive modulation
of AMPA receptors may be therapeutically effective in the
treatment of cognitive deficits. However, recent evidence
has shown that in addition to modulating fast synaptic plasticity
and memory processes, AMPA receptor potentiators alter downstream
signalling pathways and may thereby have utility in other
CNS disorders. The present review summarises studies into
the effects of AMPA receptor potentiators (with a focus on
the biarylpropylsulfonamides) in rodent models of depression
and Parkinson’s disease.
[Back to top]
Pathologically-Activated Therapeutics for Neuroprotection:
Mechanism of NMDA Receptor Block by Memantine and S Nitrosylation
S.A. Lipton
Alzheimer’s disease (AD) and Vascular dementia represent
the most common forms of dementia. If left unabated, the economic
cost of caring for patients with these maladies would consume
the entire gross national product of the industrialized world
by the middle of this century. Until recently, the only available
drugs for this condition were cholinergic treatments, which
symptomatically enhance cognitive state to some degree, but
they were not neuroprotective. Many potential neuroprotective
drugs tested in clinical trials failed because of intolerable
side effects. However, after our discovery of its clinically-tolerated
mechanism of action, one putatively neuroprotective drug,
memantine, was recently approved by the European Union and
the U.S. Food and Drug Administration (FDA) for the treatment
of dementia. Recent phase 3 clinical trials have shown that
memantine is effective in the treatment of both mild and moderate-to-severe
Alzheimer’s disease and possibly Vascular dementia (multi-infarct
dementia). Here we review the molecular mechanism of memantine’s
action and also the basis for the drug’s use in these
neurological diseases, which are mediated at least in part
by excitotoxicity. Excitotoxicity is defined as excessive
exposure to the neurotransmitter glutamate or overstimulation
of its membrane receptors, leading to neuronal injury or death.
Excitotoxic neuronal cell damage is mediated in part by overactivation
of N-methyl-D-aspartate (NMDA)-type glutamate receptors,
which results in excessive Ca2+
influx through the receptor associated ion channel and subsequent
free radical formation. Physiological NMDA receptor activity,
however, is also essential for normal neuronal function. This
means that potential neuroprotective agents that block virtually
all NMDA receptor activity will very likely have unacceptable
clinical side effects. For this reason many previous NMDA
receptor antagonists have disappointingly failed advanced
clinical trials for a number of neurodegenerative disorders.
In contrast, studies in our laboratory have shown that the
adamantane derivative, memantine, preferentially blocks excessive
NMDA receptor activity without disrupting normal activity.
Memantine does this through its action as an uncompetitive,
low-affinity, open-channel blocker; it enters the receptor-associated
ion channel preferentially when it is excessively open, and,
most importantly, its off-rate is relatively fast so that
it does not substantially accumulate in the channel to interfere
with subsequent normal synaptic transmission. Clinical use
has corroborated the prediction that memantine is well tolerated.
Besides Alzheimer’s disease, memantine is currently
in trials for additional neurological disorders, including
HIV-associated dementia, depression, glaucoma, and severe
neuropathic pain. A series of second-generation memantine
derivatives are currently in development and may prove to
have even greater neuroprotective properties than memantine.
These second-generation drugs take advantage of the fact that
the NMDA receptor has other modulatory sites in addition to
its ion channel that potentially could also be used for safe
but effective clinical intervention.
[Back to top]
The Molecular Basis of Conantokin Antagonism of NMDA
Receptor Function
M. Prorok and F.J. Castellino
The N-methyl-D-aspartate receptor (NMDAR), a subtype of ionotropic
glutamate receptor, has been implicated in a host of chronic
and acute neurological disorders. Accordingly, much emphasis
has been placed on the development of safe and effective therapeutic
agents that specifically antagonize this target. The conantokins
are a class of small, naturally occurring peptides that inhibit
ion flow through the NMDAR. Some conantokins demonstrate receptor
subunit selectivity, a pharmacological attribute of emerging
importance in the search for suitable drug candidates. The
current review summarizes the NMDAR inhibitory properties
of the conantokins, including structure-function relationships
and mechanism of action. This information is fundamental to
the rational design of suitable agents that can effectively
treat pathophysiologies linked to NMDAR dysfunction.
[Back to top]
Glycine Transporter 1 Inhibitors and Modulation of
NMDA Receptor-Mediated Excitatory Neurotransmission
C. Sur and G.G. Kinney
In the central nervous system, glutamate is essential for
a proper synaptic communication in neuronal networks supporting
critical behavioral activities such as learning and memory.
Dysfunction of glutamatergic excitatory neurotransmission
has been implicated in numerous neurological and pyschiatric
disorders and a growing body of research suggests that potentiation
of NMDA receptor function may represent a novel approach for
the treatment of schizophrenia. An actively pursued strategy
to potentiate NMDA receptor function is to increase synaptic
levels of the neurotransmitter glycine by blocking the glycine
transporter type 1 (GlyT1). Since glycine acts as a co-agonist
at the NMDA receptor, this approach could enhance the effectiveness
of normal NMDA receptor-mediated glutamatergic neurotransmission.
Recent research on the physiology of this uptake system as
well as on the development and preclinical testing of novel
GlyT1 inhibitors have greatly enhanced our knowledge of the
role of this transporter in the modulation of NMDA receptor
activity and suggested that this approach may be feasible.
Clinical studies with novel glycine reuptake inhibitors will
provide critical information regarding the validity of this
therapeutic concept for the treatment of schizophrenia and
other disorders associated with NMDA receptor hypofunction.
[Back to top]
Metabotropic Glutamate Receptors as Drug Targets
M. Récasens, J. Guiramand, R. Aimar, A. Abdulkarim
and G. Barbanel
L-glutamate (Glu), the main excitatory amino acid neurotransmitter
in the mammalian central nervous system, is involved in many
physiological functions, including learning and memory, but
also in toxic phenomena occurring in numerous degenerative
or neurological diseases. These functions mainly result from
its interaction with Glu receptors (GluRs). The broad spectrum
of roles played by glutamate derived from the large number
of membrane receptors, which are currently classified in two
main categories, ionotropic (iGluRs) and metabotropic (mGluRs)
receptors. The iGluRs are ion channels, permeant to Na+
(Ca2+) while the mGluRs belongs
to the superfamily of G-protein coupled receptors (GPCRs).
Despite continuous efforts over more than two decades, the
use of iGluR agonists or antagonists to improve or inhibit
excitatory transmission in pathological states still remains
a major challenge, though the discovery and development of
recent molecules may prove it worthwhile. This probably results
form the vital role of fast excitatory transmission in many
fundamental physiological functions. Since the discovery of
mGluRs, hope has emerged. Indeed, mGluRs are mainly involved
in the regulation of fast excitatory transmission. Consequently,
it was logically thought that modulating mGluRs with agonists
or antagonists might lead to more subtle regulation of fast
excitatory transmission than by directly blocking iGluRs.
As a result of intensive investigation, new drugs permitting
to discriminate between these receptors have emerged. Moreover,
a new class of molecules acting as negative or positive allosteric
modulators or mGluRs is now available and appears to be promising.
In the following, we will review the classification of mGluRs
and the functions in which mGluRs are involved. We will focus
on their potential as therapeutic targets for improving numerous
physiological functions and for different neurodegenerative
and neuropsychiatric disorders, which are related to malfunction
of Glu signaling in human beings.
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