Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 8, 2006
Contents
NMDA Receptors as Targets in Medicinal Chemistry
Guest Editor: Dr. William Metz
Editorial Pp. 747-748
N-Methyl-D-Aspartate Receptor (NMDA) Antagonists
as Potential Pain Therapeutics Pp. 749-770
Dean G. Brown and Johannes J. Krupp
[Abstract]
Progress Towards Validating the NMDA Receptor Hypofunction
Hypothesis of Schizophrenia Pp. 771-785
Craig W. Lindsley, William D. Shipe, Scott E. Wolkenberg,
Cory R. Theberge,David L. Williams Jr, Cyrille Sur and Gene
G. Kinney
[Abstract]
Survival Signaling Pathways Activated by NMDA Receptors
Pp. 787-799
Michal Hetman and Giorgi Kharebava
[Abstract]
The NMDA/D1 Receptor Complex as a New Target in Drug
Development Pp. 801-808
Cristina Missale, Chiara Fiorentini, Chiara Busi, Ginetta
Collo and P.F. Spano
[Abstract]
Competitive Gly/NMDA Receptor Antagonists Pp.
809-821
Daniela Catarzi, Vittoria Colotta and Flavia Varano
[Abstract]
Can Selective Ligands for Glutamate Binding Proteins
be Rationally Designed? Pp. 823-847
Nicholas R. Natale, Kathy R. Magnusson and Jared
K. Nelson
[Abstract]
Abstracts
[Back to top]
Editorial
The N-methyl-D-aspartate (NMDA) receptor is
a major excitatory neurotransmitter receptor in the human
brain and central nervous system. Over activation of this
receptor as a result of a neurodegenerative event, such as
cerebral ischemia or neurotrauma, has been implicated in acute
disorders such as stroke. The NMDA receptor has also been
linked to other progressive diseases such as Alzheimer, Parkinson,
and Huntington. Thus, the quest to discover a small molecule
that can regulate the NMDA receptor remains a challenging
task in CNS drug discovery.
This special issue of CTMC highlights the progress and recent
advances in research and development involving the NMDA receptor.
It is a collection of reviews authored and submitted by eminent
researchers who have made significant contributions in this
field.
Dr. Sui Xiong Cai was personally involved in the research
and discovery of ACEA-1021 a glycine/NMDA receptor antagonist
and related compounds such as ACEA-1416. He provides insight
into the pharmacology of these antagonists for clinical development
and their potential therapeutic applications for the treatment
of traumatic brain injury, pain, cocaine overdose and convulsions.
Several authors focused their reviews on the subunit composition
of the NMDA receptor. The NR2B subtype-selective NMDA antagonists
have been an area of intense investigation in medicinal research
since their discovery nearly two decades ago. The article
submitted by Dr. André Schrattenholz and Vukic Soskic´
summarizes several general aspects of NMDA receptors and potential
disease targets for drug development. Central to their review
is the discussion on the functional regulation of NMDA receptors
with respect to the NR2 subunits. Drs. István Borza
and György Domány provide an account of the discovery
of ifenprodil. Their review describes the design of selective
NR2B antagonists using the pharmacophore of ifenprodil. On
the other hand, Dr. Mark Layton, Michael Kelly and Kevin Rodzinak
discuss recent efforts in the discovery and development of
structurally unique NR2B subtype-selective NMDA antagonists
that do not fit the classical “ifenprodil-like”
pharmacophore. They provide a complete overview on the most
recent developments on NR2B subtype-selective NMDA antagonists,
including a comprehensive survey of the most recent literature.
Professor Mingjie Zhang, Wenyu Wen and Wenning Wang discuss
targeting the proteins and enzymes down stream of the NMDA
receptor-signaling pathway. They specifically review the PDZ
domain of PSD-95 and the critical role it plays in the NMDA
receptor/neuronal nitric oxide synthase pathway. The authors
provide recent results on flavonoids from Scutellaria
baicalensis extracts, which bind to a pocket of the PDZ2
domain overlapping with the NR2B subunit-binding surface and
provide convincing evidence that small molecules targeting
the PDZ domain of PSD-95 could be a useful strategy for inhibition
of glutamate-induced excitotoxicity.
Professor Bernhard Wünsch and Michael Sax provide a comprehensive
summary of the structure and NMDA receptor binding affinity
of dexoxadrol, etoxadrol and their derivatives. The authors
discuss the potential mechanism of the interactions between
dexoxadrol and etoxadrol and the phencyclidine (PCP) binding
site of the NMDA receptor, providing valuable insight into
the development of NMDA receptor modulating compounds.
Dr. Ryu Nagata and co-workers review significant contributions
in the discovery of antagonists for the glycine-binding site
of the NMDA receptor. In particular, they focus on the in
vivo activity of antagonists from the tricyclic quinoxalinedione
and indole-2-carboxylic acid series of compounds that have
zwitterionic functionality.
Drs. Dean Brown and Johannes Krupp provide a current assessment
and comprehensive review of the potential clinical utility
of NMDA antagonists for pain therapy, which is currently one
of the most important and hotly contested areas in the field
of the NMDA receptors. Many structurally diverse NMDA antagonists
have been reported to have activity in both animal models
and clinical models of neuropathic pain, although side effects
have severely limited the clinical utility of these as potential
therapeutics. The authors provide a current assessment of
the potential clinical utility of representative examples
of NMDA antagonists (i.e. glycine-site, NR2B sites and weak-binding
channel blockers) that have demonstrated improved side effect
profiles in animal models of pain.
Dr. Craig Lindsley and co-workers describe recent progress
towards validation of the NMDA receptor hypofunction hypothesis
of schizophrenia in preclinical models. Historically, treatment
for schizophrenic patients has centered on D2 dopamine receptor
antagonists. This review presents the NMDA receptor as an
emerging target for the development of novel antipsychotic
agents, including a discussion of the progress towards in
vivo target validation with GlyT1 inhibitors and mGluR5 positive
allosteric modulators.
NMDA receptor signaling plays an important role in neuronal
survival and neuroprotection. Professor Michal Hetman and
Giorgi Kharebava provide a review that helps clarify a complex
problem: the development of NMDA receptor antagonists that
are selective for the exocytotoxic activity of the NMDA, yet
will not antagonize the modes of neuroprotection offered by
NMDA receptor stimulation. The protective role of transcription
factors is also discussed. Professor Cristina Missale and
co-workers discuss the importance of defining direct interactions
between NMDA and dopamine D1 and the possible implications
for novel therapeutic strategies to modify dopaminergic and
glutamatergic neurotransmissions. The molecular mechanism,
functional implication and pharmacological significance of
D1/NMDA interaction via direct protein-protein oligomerization
are discussed as an innovative approach for therapeutic intervention.
Prof. Daniela Catarzi, Vittoria Colotta and Flavia Varano
provide a comprehensive overview of the development of glycine
antagonists of the NMDA receptor, including significant work
from the authors’ laboratories. They particularly discuss
competitive Gly/NMDA receptor antagonists with particular
attention not only to recently designed compounds but also
to previously developed derivatives that are actually under
investigation for their potential therapeutic applications.
Prof. Nicholas Natale, Kathy Magnusson and Jared Nelson ask
the question “Can Selective Ligands for Glutamate Binding
Proteins be Rationally Designed?”, then provide many
examples in an attempt to answer that question. The paper
provides information on SAR studies for many different receptor
systems and summarizes the major advances in glutamate binding
proteins as a pharmacological target outlining the many therapeutic
opportunities.
In summary, the authors provide a diverse and interesting
range of topics for discussion, all related to the NMDA receptor.
It remains for me to thank the people responsible for the
realization of this symposium-in-print. I would like to thank
Dr. Allen Reitz for his kind invitation to guest edit this
issue and Ms. Barbara Calhoun for her editorial assistance.
I am especially indebted to all of the authors for their excellent
contributions to this special issue. Their commitment of time
and effort for researching, writing, editing and, in some
cases, refereeing truly produced a volume of work that will
be of great value to researchers in the field.
William A. Metz, PhD.
CNS Discovery Chemistry
Sanofi Aventis
N103A
Rt 202-206
Bridgewater, NJ 08807-0800,
USA
[Back to top]
N-Methyl-D-Aspartate Receptor (NMDA) Antagonists
as Potential Pain Therapeutics
Dean G. Brown and Johannes J. Krupp
NMDA receptors are known to be involved in nociceptive transmission
and pain processing. Many structurally diverse NMDA antagonists
have been reported to have activity in both animal models
and clinical models of neuropathic pain. Untoward side effects
such as ataxia and sedation have severely limited the clinical
uses of this class of potential therapeutics. However, antagonists
at the glycine-site, NR2B sites and weak-binding channel blockers
have demonstrated an improved side effect profile in animal
models of pain. These types of compounds may hold potential
promise for future pain therapies. This review covers reported
pain data surrounding representative examples of NMDA antagonists
and provides a current assessment of potential clinical utility.
[Back to top]
Progress Towards Validating the NMDA Receptor Hypofunction
Hypothesis of Schizophrenia
Craig W. Lindsley, William D. Shipe, Scott E. Wolkenberg,
Cory R. Theberge,David L. Williams Jr, Cyrille Sur and Gene
G. Kinney
This article describes recent progress towards validation
of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis
of schizophrenia in preclinical models. Schizophrenia, a complex
disease characterized by positive, negative and cognitive
symptoms, affects 1% of the world population and requires
lifelong, daily maintenance therapy. For the last several
decades, thinking in this field has been dominated by the
hypothesis that hyperfunction of dopamine pathways played
a key role in schizophrenia. However, the therapeutic agents
developed from this hypothesis have a slow onset of action
and tend to improve only the positive symptoms of the disease.
The NMDA receptor antagonist PCP has been shown to induce
the positive, negative and cognitive symptoms of schizophrenia
in healthy patients and cause a resurgence of symptoms in
stable patients. These observations led to the NMDA receptor
hypofunction hypothesis as an alternative theory for the underlying
cause of schizophrenia. According to this hypothesis, any
agent that can potentiate NMDA receptor currents has the potential
to ameliorate the symptoms of schizophrenia. To date, NMDA
receptor currents can be modulated by either direct action
on modulatory sites on the NMDA receptor (i.e., the glycine
co-agonist binding site) or indirectly by activation of G-protein
coupled receptors (GPCRs) known to potentiate NMDA receptor
function (i.e., mGluR5). This review will discuss the NMDA
receptor hypofunction hypothesis, the NMDA receptor as an
emerging target for the development of novel antipsychotic
agents and progress towards in vivo target validation
with GlyT1 inhibitors and mGluR5 positive allosteric modulators.
Other potential targets for modulating NMDA receptor currents
(polyamine sites, muscarinic receptors, etc…) will also
be addressed briefly.
[Back to top]
Survival Signaling Pathways Activated by NMDA Receptors
Michal Hetman and Giorgi Kharebava
N-methyl-D-aspartate receptors (NMDAR) have
a recognized role in neuronal plasticity while their excessive
activation results in excitotoxic death. Therefore, NMDAR
antagonists are considered for neuroprotective interventions.
However, there is also an emerging role of NMDAR in supporting
neuronal survival. Thus, during CNS development, basal NMDAR
activity suppresses neuronal apoptosis while moderate NMDAR
activation may, at least under some conditions, protect against
excitotoxic/ischemic insults. These suggest that while protecting
from excitotoxicity, NMDAR antagonists would also reduce pro-survival
activity of NMDAR. Hence, the identification of the switches
controlling pro-survival vs. pro-excitotoxic outcome of NMDAR
stimulation may lead to development of NMDAR antagonists that
selectively block the excitotoxicity while enhancing the protective
NMDAR signaling. On the other hand, the existence of anti-apoptotic/pro-proliferative
NMDAR signaling in transformed cells may result in new strategies
to attack cancer. This review focuses on the emerging field
of neuroprotective signaling mediators that are implicated
in pro-survival activity of NMDAR. We discuss the evidence
implicating either NR2B or nonNR2B NMDAR in mediating the
protection. We also present the reports linking NMDAR-mediated
protection to the activation of survival signaling kinases
including ERK and Akt, or suppression of a pro-apoptotic kinase,
GSK-3β.
The protective role of transcription factors is also discussed.
Finally, we review the existing evidence suggesting that NMDAR
support survival by regulating the pro-survival trophic factor
signaling and/or the cell death machinery. Although NMDAR
provide a major survival input to CNS neurons, the NMDAR-activated
protective signaling is poorly understood and, therefore,
deserves further research effort.
[Back to top]
The NMDA/D1 Receptor Complex as a New Target in Drug
Development
Cristina Missale, Chiara Fiorentini, Chiara Busi, Ginetta
Collo and P.F. Spano
Dopamine and glutamate have been shown to extensively
interact in the striatum, nucleus accumbens, hippocampus and
prefrontal cortex, to regulate different physiological functions,
including locomotor activity, positive reinforcement, attention
and working memory. Although dysfunctions of dopamine transmission
have long been identified as critical determinants of neurological
and neuropsychiatric disorders, such as Parkinson’s
disease and schizophrenia, there is now increasing evidence
that concurrent alterations of dopamine and glutamate function
may play a central role in the pathophysiology of these diseases.
Thus, defining the characteristics of dopamine-glutamate interactions
may be crucial to identify alternative molecular targets for
the development of novel pharmacological tools. At the postsynaptic
level, interactions between the dopamine D1 and the glutamate
NMDA receptors appear to be particularly relevant. Different
mechanisms are involved in this interactions: 1) D1R-dependent,
second messenger-mediated phosphorylation of NMDAR subunits;
2) coordinated regulation of receptor trafficking at synaptic
sites; 3) formation of an heteromeric D1/NMDA receptor complex.
In this paper we review the molecular mechanisms, functional
implications and pharmacological significance of D1R/NMDAR
interaction via direct protein-protein oligomerization.
[Back to top]
Competitive Gly/NMDA Receptor Antagonists
Daniela Catarzi, Vittoria Colotta and Flavia Varano
Glutamic acid (Glu) is the major excitatory neurotransmitter
in the mammalian central nervous system (CNS) where it is
involved in the physiological regulation of different processes.
It has been well established that excessive endogenous Glu
is associated with many acute and chronic neurodegenerative
disorders such as cerebral ischemia, epilepsy, amiotrophic
lateral sclerosis (ALS), Parkinson’s and Alzheimer’s
diseases. In addition to the classical competitive glutamate
receptor (GluR) antagonists, much effort has been directed
toward the development of many different non-competitive antagonists
of these receptors and, among them, compounds blocking the
glycine site on the NMDA receptor complex (Gly/NMDA) have
been widely investigated. Many Gly/NMDA receptor antagonists
showed to be potential therapeutic agents in many neurological
diseases such as stroke, epilepsy and neuropathic pain. Some
of them, endowed also with favourable physicochemical properties
and low secondary undesiderable effects, reached clinical
trials.
[Back to top]
Can Selective Ligands for Glutamate Binding Proteins
be Rationally Designed?
Nicholas R. Natale, Kathy R. Magnusson and Jared
K. Nelson
A major neurotransmitter, L-Glutamate must be stored, transported
and received, and these processes are mediated by proteins
that bind this simple yet essential amino acid. Detailed evidence
continues to emerge on the structure of Glu binding proteins,
which includes both receptors and transporters. It appears
that receptors and transporters bind to Glu in different conformations,
which may present a pharmacological opportunity. This review
will compare and contrast information available on Glu Receptors
(AMPA, NMDA, KA and mGlu), excitatory amino acid transporters
(EAATs), the system Xc- transporter (XCT) and the vesicular
Glutamate transporter (GVT). The cross-reactivity of ligands
which have been previously used to characterize the glutamate
binding proteins with system Xc- raises some fundamental interpretational
issues regarding the mechanisms through which these analogues
produce CNS damage. Although at one time it was thought that
unraveling selectivity among glutamate binding proteins was
an intractable problem, recently the NMDA antagonist (memantine)
has been approved for general medical practice for treatment
of Alzheimer’s disease. Two other agents are in advanced
clinical trials: an Ampakine for potential improvement of
cognitive disorders, and a selective mGlu agonist for treatment
of anxiety. The prospects for unraveling cross-reactivity
will be weighed in light of a critical comparison of the glutamate
binding protein targets.
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