Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 7, 2006
Contents
NMDA Receptors as Targets in Medicinal Chemistry
Guest Editor: Dr. William Metz
Editorial Pp. 649-650
Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic
Agents: ACEA-1021 and Related Compounds Pp.651-662
Sui Xiong Cai
[Abstract]
NMDA Receptors are not Alone: Dynamic Regulation of
NMDA Receptor Structure and Function by Neuregulins and Transient
Cholesterol-Rich Membrane Domains Leads to Disease-Specific
Nuances of Glutamate-Signalling Pp. 663-686
André Schrattenholz and Vukic Soskic´
[Abstract]
NR2B Selective NMDA Antagonists: The Evolution of
the Ifenprodil-Type Pharmacophore Pp. 687-695
István Borza and György Domány
[Abstract]
Recent Advances in the Development of NR2B Subtype-Selective
NMDA Receptor Antagonists Pp. 697-709
Mark E. Layton, Michael J. Kelly III and Kevin J. Rodzinak
[Abstract]
Targeting PDZ Domain Proteins for Treating NMDA Receptor
Mediated Excitotoxicity Pp. 711-721
Wenyu Wen, Wenning Wang and Mingjie Zhang
[Abstract]
Relationships Between the Structure of Dexoxadrol
and Etoxadrol Analogues and their NMDA Receptor Affinity
Pp. 723-732
Michael Sax and Bernhard Wünsch
[Abstract]
Tricyclic Quinoxalinediones, Aza-kynurenic
Acids, and Indole-2 Carboxylic Acids as In Vivo Active
NMDA-Glycine Antagonists Pp. 733-745
Ryu Nagata, Seiji Katayama, Ken-ichi Ohtani, Hiroyasu
Tanaka and Kozo Shimago
[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]
Glycine/NMDA Receptor Antagonists as Potential CNS
Therapeutic Agents: ACEA-1021 and Related Compounds
Sui Xiong Cai
Glutamate is the main excitatory neurotransmitter in central
nervous system (CNS) and NMDA receptors are one of the major
classes of ionotropic glutamate receptors. NMDA receptors
have been known to play critical roles in normal CNS activities,
as well as in many pathological conditions, including both
acute and chronic diseases. The discovery of glycine as a
coagonist of NMDA receptors has led to intensive research
of glycine/NMDA antagonists as potential CNS drugs. The robust
efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5),
in animal model of brain ischemia, together with good safety
profile in animal models and in clinical trials, suggested
that this class of NMDA antagonists should have good chance
of success in the clinic as neuroprotectants. The clinical
trial of ACEA-1021 for stroke was discontinued, mainly due
to low solubility and lack of metabolism of the drug that
led to the observation of crystals in the urine of some of
the patients. However, through SAR studies, compounds such
as ACEA-1416 (10) have been identified with improved properties,
such as higher in vivo potency and site for potential
metabolism. Therefore these compounds should be able to overcome
some of the liabilities of ACEA-1021 and potentially could
be developed as neuroprotectants. Based on the preclinical
and clinical studies of glycine/NMDA antagonists, as well
as the clinical experiences with t-PA, initiation of treatment
within a short time window after the onset of stroke could
be critical for the success of these antagonists in clinical
trials. This can be accomplished by implementing the procedure
developed for t-PA clinical trials, with modification based
on the safety profile of glycine/NMDA antagonists, for future
clinical trial to administer the drug as soon as possible
after stroke onset. In addition, glycine/NMDA antagonists
also have other potential therapeutic applications, such as
for the treatment of traumatic brain injury, pain, cocaine
overdose and convulsions.
[Back to top]
NMDA Receptors are not Alone: Dynamic Regulation of
NMDA Receptor Structure and Function by Neuregulins and Transient
Cholesterol-Rich Membrane Domains Leads to Disease-Specific
Nuances of Glutamate-Signalling
André Schrattenholz and Vukic Soskic
Glutamate receptors of the N-methyl-D-asparate
(NMDA-) subtype are tetrameric allosteric and ligand-gated
calcium channels. They are modulated by a variety of endogenous
ligands and ions and play a pivotal role in memory-related
signal transduction due to a voltage-dependent block by magnesium,
which makes them Hebbian coincidence detectors. On the structural
level NMDA receptors have an enormous flexibility due to seven
genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing
and extensive posttranslational modifications, like phosphorylation
and glycosylation. NMDA receptors are thought to be responsible
for excitotoxicity and subsequent downstream events like neuroinflammation
and apoptosis and thus have been implicated in many important
human pathologies, ranging from amyotrophic lateral sclerosis,
Alzheimer’s and Parkinson’ disease, depression,
epilepsy, trauma and stroke to schizophrenia. This fundamental
significance of NMDA receptor-related excitotoxicity is discussed
in the context of the developing clinical success of Memantine,
but moreover set into relation to various proteomic and genetic
markers of said diseases. The very complex localisational
and functional regulation of NMDA receptors appears to be
dependent on neuregulins and receptor tyrosine kinases in
cholesterol-rich membrane domains (lipid rafts), calcium-related
mitochondrial feedback-loops and subsynaptic structural elements
like PSD-95 (post-synaptic density protein of 95 kD). The
flexibility and multitude of interaction partners and possibilities
of these highly dynamic molecular systems are discussed in
terms of drug development strategies, in particular comparing
high affinity and sub-type specific ligands to currently successful
or promising therapies.
[Back to top]
NR2B Selective NMDA Antagonists: The Evolution of
the Ifenprodil-Type Pharmacophore
István Borza and György Domány
The quest for NR2B subtype selective NMDA
antagonists started almost twenty years ago. The structure
of ifenprodil, the prototype of this group of compounds, inspired
many medicinal chemists in several research units. Different
approaches led to the identification of the pharmacophore
and several distinct classes of compounds containing this
pharmacophore. From these studies a few drug candidates emerged
and clinical trials proved the viability of the concept. This
article attempted to follow the evolution from ifenprodil,
a multiple ligand, to selective NR2B antagonists.
[Back to top]
Recent Advances in the Development of NR2B Subtype-Selective
NMDA Receptor Antagonists
Mark E. Layton, Michael J. Kelly III and Kevin J. Rodzinak
Over activation of the NMDA receptor complex has been
implicated in a number of neurological conditions. The use
of NMDA antagonists as therapeutic agents has been limited
by serious cognitive and motor side effects. Significant efforts
have been reported in the development of NR2B subtype-selective
antagonists, which have shown efficacy without the side effects
observed with nonspecific NMDA antagonists. Classical ifenprodil-like
molecules containing benzyl- and phenylpiperidines attached
to a phenol or an appropriate isostere by a linker have provided
valuable chemical leads as potential therapeutic agents. In
this review, recent efforts in the discovery and development
of structurally unique NR2B subtype-selective NMDA antagonists
that do not fit the classical “ifenprodil-like”
pharmacophore will be discussed.
[Back to top]
Targeting PDZ Domain Proteins for Treating NMDA Receptor
Mediated Excitotoxicity
Wenyu Wen, Wenning Wang and Mingjie Zhang
N-methyl-D-aspartate (NMDA)
receptors play essential roles in the normal physiology of
neurons, and these receptors are also largely responsible
for glutamate-induced excitotoxicity. Since treatments of
glutamate-induced excitotoxicity by NMDA receptor inhibitors
often result in adverse side effects, alternative treatment
approaches have been actively sought in recent years. One
potential approach is to target proteins and enzymes down
stream of the NMDA receptor signaling pathways. Extensive
studies in recent years have demonstrated that PDZ domains
of PSD-95 play critical roles in scaffolding the NMDA receptor/neuronal
nitric oxide synthase pathway. Therefore, PSD-95 PDZ domains
become attractive targets for treatment of glutamate-induced
overproduction of nitric oxide. The strategy is to develop
small compounds that can effectively block protein-protein
interactions mediated by the PDZ domains of PSD-95. Biochemical
and structural studies of PDZ/target interactions have indicated
that developing small molecules to compete with PDZ targets
is a feasible approach. We provide an example demonstrating
the discovery and further development of small molecules capable
of disrupting PSD-95/NMDA receptor and/or PSD-95/neuronal
nitric oxide synthase complexes.
[Back to top]
Relationships Between the Structure of Dexoxadrol
and Etoxadrol Analogues and their NMDA Receptor Affinity
Michael Sax and Bernhard Wünsch
In the mid 1960s the (dioxolan-4-yl)piperidine derivatives
dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a)
were synthesized. Their pharmacological potential as analgesics,
anesthetics and local anesthetics was evaluated in animal
models and later on in clinical trials with patients. However,
severe side effects including psychotomimetic effects, unpleasant
dreams and aberrations stopped the clinical evaluation of
dexoxadrol and etoxadrol. Both dioxolane derivatives represent
NMDA receptor antagonists, which possess high affinity to
the phencyclidine binding site within the NMDA receptor associated
ion channel. In this review relationships between the structure
of acetalic dexoxadrol analogues and homologues and their
affinity toward the phencyclidine binding site of the NMDA
receptor are summarized. In particular, high affinity is attained
with compounds bearing two phenyl residues or one phenyl residue
and an alkyl residue with two or three carbon atoms at the
acetalic center. At least one oxygen atom of the oxygen heterocycle
is necessary. Instead of the entire piperidine ring aminoalkyl
substructures are sufficient for strong receptor interactions.
Compounds with a primary amino moiety generally display the
highest receptor affinity, whereas tertiary amines possess
low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane
ring or elongation of the oxygen heterocycle / amino group
distance results in compounds with considerable NMDA receptor
affinity.
[Back to top]
Tricyclic Quinoxalinediones, Aza-kynurenic Acids,
and Indole-2 Carboxylic Acids as In Vivo Active NMDA-Glycine
Antagonists
Ryu Nagata, Seiji Katayama, Ken-ichi Ohtani, Hiroyasu
Tanaka and Kozo Shimago
This review article describes the development of in vivo
active antagonists for the glycine binding site of the N-Methyl-D-Aspartate
(NMDA) receptor. There were several difficulties in identifying
a class of antagonists with in vivo efficacy and
only a few compounds succeeded in emerging with activity in
vivo. A series of tricyclic quinoxalinediones was highly
potent glycine antagonists in vitro and the derivatives
having a zwitterionic moiety including SM-18400 indeed showed
in vivo activity. Similarly, tricyclic indole-2-carboxylic
acids having a zwitterionic moiety such as SM-31900 were also
active in vivo. In fact, SM-18400 and SM-31900 exhibited
efficacy in several animal stroke models using intravenous
infusion protocols. The practical syntheses of SM-18400 and
SM-31900 as well as the novel synthesis of moderately active
glycine antagonists, tricyclic azakynurenic acids, were also
developed.
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