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Current
Topics in Medicinal Chemistry
ISSN:1568-0266
Current Topics
in Medicinal Chemistry
Volume 10, Number 2, 2010
Contents
Current Approaches for the Treatment of
Cognitive Deficits in CNS Disease
Guest Editor: Robert L. Hudkins
Editorial Pp. 142-143
Neuronal Nicotinic Acetylcholine Receptors - Targets
for the Development of Drugs to Treat Cognitive Impairment
Associated with Schizophrenia and Alzheimer’s Disease
Pp. 144-152
Simon N. Haydar and John Dunlop
[Abstract] [Purchase
Article]
Histamine H3 Antagonists
for Treatment of Cognitive Deficitsin CNS Diseases
Pp. 153-169
Rita Raddatz, Ming Tao and Robert L. Hudkins
[Abstract] [Purchase
Article]
Recent Progress in the Discovery of Non-Sarcosine
Based GlyT1 Inhibitors Pp. 170-186
Scott E. Wolkenberg and Cyrille Sur
[Abstract] [Purchase
Article]
Metabotropic Glutamate Receptors as Therapeutic Targets for
Cognitive Disorders Pp. 187-206
A. Gravius, M. Pietraszek, A. Dekundy and W.
Danysz
[Abstract] [Purchase
Article]
5-HT6 Receptor Antagonists
as Potential Therapeuticsfor Cognitive Impairment Pp.
207-221
Gérard Rossé and Hervé
Schaffhauser
[Abstract] [Purchase
Article]
Phosphodiesterase Inhibitors as Potential Cognition Enhancing
Agents Pp. 222-230
Christopher J. Schmidt
[Abstract] [Purchase
Article]
Abstracts
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Editorial: Current Approaches for the Treatment of
Cognitive Deficits in CNS Disease
Research in the field of cognition is currently a high
priority as the elderly population increases, with a great
need to discover and develop new drugs to treat age-related
cognitive disorders, including dementias as well as cognitive
impairments associated with neuropsychiatric disorders, such
as schizophrenia. Various aspects of cognitive dysfunction
also occur in association with several CNS disorders, including
Parkinson’s disease, AIDS-associated dementia, stroke,
stress, sleep deprivation, depression, and anxiety. Cognition
is a complex set of processes, including attention, perception,
emotion, learning and memory, action, and problem solving.
Drugs currently approved for use in the treatment of neurodegenerative
disorders, such as Alzheimer’s disease (AD), include
the cholinesterase inhibitors donepezil, rivastigmine, and
galantamine, and memantine, a partial agonist at glutamate
receptors. Since none of these drugs works particularly well
in treating the symptoms of AD, a variety of new drug discovery
approaches and chemical entities are currently being explored
to identify new cognitive enhancers. This special issue will
review a few of the key contemporary targets that are being
pursued in discovery research that are either at the late-preclinical
stage or are in clinical evaluation to treat cognitive deficits
of various CNS diseases.
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated
cationic-channels that are highly expressed in the CNS. The
α7
and α4/β2
subtypes are involved in cognition and attention, and are
highly expressed in brain regions involved in learning and
memory, including the hippocampus, thalamus and cortex. nAChRs
are involved directly and indirectly in release of neurotransmitters
including acetylcholine, dopamine, glutamate and norepinephrine,
and in AD and schizophrenia, levels of cortical nAChRs are
decreased. In the first review in this issue Haydar and Dunlop
review intense drug discovery efforts focused on the development
of α7
and α4/β2
nAChR agonists and, more recently, positive allosteric modulators
(PAMs) of the α7nAChR
as potential therapeutic agents.
Histamine H3 receptors (H3R)
are expressed predominatly in the brain, localized to the
cerebral cortex, amygdala, hippocampus, striatum, thalamus
and hypothalamus, where they are expressed on presynaptic
terminals and function as inhibitory auto- and hetero-receptors.
H3 antagonists increase the
release of various neurotransmitters, including histamine,
ACh, NE, 5-HT and DA, and have potential utility in treating
cognitive deficits associated with various dementias and schizophrenia.
In the second review, Raddatz, Tao and Hudkins review the
H3R biology and recent drug
discovery efforts as NCEs with reduced side effect liabilities
have been identified and advanced into clinical evaluation.
Glycine is a major inhibitory neurotransmitter in the brain
acting via ligand-gated strychnine-sensitive glycine-A receptors.
It also acts as a required positive allosteric modulator of
glutamate by binding to the glycine-B site on the NMDA receptor,
which facilitates glutamate binding to the NMDA complex and
enhances excitatory transmission in cortex and hippocampus.
Based on the involvement of NMDA receptor-mediated neurotransmission
in processes such as cognition, pharmacological manipulation
of extracellular synaptic glycine is an active area of research
to develop novel treatments for neuropsychiatric disorders.
A key component of cerebral glycine metabolism and regulation
of synaptic glycine levels is the glycine transporter type
1 (GlyT1). Blockade of GlyT1 to elevate extracellular synaptic
glycine concentrations has been hypothesized to potentiate
NMDA receptor function in vivo, and represents a
rational approach for the treatment of schizophrenia and cognitive
disorders. In the next article, Wolkenberg and Sur review
the large body of scientific evidence supporting this hypothesis,
and the drug discovery efforts to develop potent and selective
GlyT1 inhibitors.
Metabotropic glutamate receptors (mGluRs) have important roles
in synaptic activity in the CNS, and ligands for group I and
II mGluRs have been proposed as promising candidates for the
treatment of cognitive disorders such as schizophrenia, Fragile
X syndrome, Alzheimer’s and Parkinson’s diseases,
and post traumatic stress disorder. The fourth paper in this
issue by Andreas Gravius et al. reviews relevant
data on the role of specific mGluRs in learning and cognitive
processes, focusing on their utility as targets for cognition
enhancement in CNS diseases.
The 5-HT6 receptor is expressed
almost exclusively in the CNS, where blockade of the receptor
function increases cholinergic and glutaminergic transmission
and in vivo cognitive efficacy in rodent behavior
models. Atypical antipsychotics, such as clozapine and olanzapine,
bind with high affinity as inverse agonists at 5-HT6
receptors, which coupled with its distribution in key brain
areas involved in learning and memory, has enhanced interest
in identifying clinical candidates for this target. The review
by Rossé and Schaffhauser examines the structure-activity-relationships
and the design of novel 5-HT6
receptor ligands and their potential use for the treatment
of cognitive impairment.
Phosphodiesterases (PDEs) function to hydrolyze the phosphodiester
bond and degrade the key second messengers, cyclic adenosine
monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)
to control their intracellular levels. The cAMP response element-binding
protein (CREB) is a required process in formation of long-term
memory and PDE inhibition has been associated with consolidation
and retention of LTP in the hippocampus and increased phosphorylation
of CREB. PDEs are highly expressed in the CNS and as reviewed
by Chris Schmidt, evidence is provided that suggests PDE1B,
PDE2, PDE4, PDE5, PDE9 and PDE10 may have therapeutic potential
for treating cognitive disorders.
I express my sincere gratitude to all the authors that contributed
to this special issue of Current Topics in Medicinal Chemistry.
My hope is that this issue will serve the cognition field
as an informative and ongoing contribution as we all await
positive outcomes from the many new approaches in clinical
trials.
Robert L. Hudkins, Ph.D.
Distinguished Scientist II
Medicinal Chemistry
Cephalon, Inc.
145 Brandywine Parkway
West Chester, PA 19380,
USA
Tel: 610.738.6283
E-mail: rhudkins@cephalon.com
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Article]
Neuronal Nicotinic Acetylcholine Receptors - Targets
for theDevelopment of Drugs to Treat Cognitive Impairment
Associated with Schizophrenia and Alzheimer’s Disease
Simon N. Haydar and John Dunlop
Nicotinic acetylcholine receptors (nAChR) have been strongly
implicated as therapeutic targets for treating cognitive deficits
in disorders such as schizophrenia and Alzheimer's disease
(AD). In particular α7
and α4β2
subtype-selective nAChR agonists and partial agonists have
been developed as potential candidates for the treatment of
schizophrenia, cognitive disorders (including Alzheimer’s
disease), and inflammation. Further development of positive
allosteric modulators were also recently reported in the literature.
In this review we will cover recent developments focused on
the above mentioned nAChR subtypes, starting from the most
advanced clinical candidate followed by an overview of literature
compounds where potency, selectivity, central nervous system
access, pharmacological activity and pharmacokinetic properties
are disclosed.
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Article]
Histamine H3 Antagonists
for Treatment of Cognitive Deficitsin CNS Diseases
Rita Raddatz, Ming Tao and Robert L. Hudkins
The H3
histamine receptor is expressed in many brain regions, including
those involved in sleep/wake regulation and cognitive functions.
Inhibition of the H3
receptor leads to increased release of multiple neurotransmitters
in these regions, making this receptor an ideal target for
the potential enhancement of arousal and/or cognitive processes.
The high interest level by several pharmaceutical companies
in H3 receptors
as potential drug targets has produced rapid advancement in
novel compound series with different properties, providing
a variety of preclinical tools as well as advancing several
candidates into clinical trials. Multiple chemotypes have
demonstrated efficacy in preclinical models covering a range
of cognitive deficits, suggesting the potential value of H3
antagonists as cognition enhancers in a variety of disease
states. These studies have revealed the actions of this class
of compounds at the cellular, neuronal systems and behavioral
levels. Recently, compounds with improved selectivity, pharmacokinetics
and preclinical safety profiles have advanced into clinical
trials for a number of potential indications. The results
of these clinical trials are eagerly awaited and will increase
our understanding of the properties of H3
receptor antagonists that will provide therapeutic value.
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Recent Progress in the Discovery of Non-Sarcosine
Based GlyT1 Inhibitors
Scott E. Wolkenberg and Cyrille Sur
The simple amino acid glycine is implicated in both inhibitory
and excitatory neurotransmission in mammalian central nervous
system, and it modulates excitatory neurotransmission through
its role as a necessary co-agonist for glutamatergic N-methyl-D-aspartate
(NMDA) receptors. Given the involvement of NMDA receptor-mediated
neurotransmission in complex cerebral processes such as cognition,
pharmacological manipulation of extracellular synaptic glycine
biology is an active area of pharmaceutical research to develop
novel treatments for neuropsychiatric disorders. A key component
of cerebral glycine metabolism is the glycine transporter
type 1 (GlyT1) and elevation of extracellular synaptic glycine
concentration by blockade of GlyT1 has been hypothesized to
potentiate NMDA receptor function in vivo and to
represent a rational approach for the treatment of schizophrenia
and cognitive disorders. The present article will review the
wealth of scientific evidence supporting that hypothesis and
the medicinal chemistry effort by many pharmaceutical companies
and academic institutions to develop potent and selective
GlyT1 inhibitors.
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Article]
Metabotropic Glutamate Receptors as Therapeutic Targets
for Cognitive Disorders
A. Gravius, M. Pietraszek, A. Dekundy and W.
Danysz
Since more than one decade, metabotropic glutamate receptors
have been under investigation as targets for various CNS disorders
such as anxiety, pain, depression, schizophrenia, Alzheimer´s
disease and Parkinson´s disease. It has been shown that
some mGluRs play a crucial role in cognitive processes such
as learning and memory, which was initially, demonstrated
using knockout mice for each receptor subtype. Later, selective
pharmacological tools were developed allowing more specific
examinations of the involvement of mGluR1-8 in various forms
of learning and memory. Ligands for group I and II mGluRs
have been proposed as promising candidates for the treatment
of cognitive disorders such as schizophrenia, Fragile X syndrome,
Alzheimer´s and Parkinson´s disease and posttraumatic
stress disorder, of which some have made it to clinical testing.
The present paper reviews relevant data on the role of mGluRs
in learning and cognition processes focusing on their utility
as targets for cognition enhancement in several CNS diseases.
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Article]
5-HT6 Receptor Antagonists
as Potential Therapeuticsfor Cognitive Impairment
Gérard Rossé and Hervé
Schaffhauser
Cognitive impairment (CI) has been recognized as a core feature
of Alzheimer’s disease (AD) and schizophrenia. The 5-HT6
receptor is an attractive target for the development of cognitive
enhancers due to its unique localization and pharmacology.
5-HT6 receptor antagonists
have been shown to modulate multiple neurotransmitter systems
and therefore enhance cognition in preclinical studies. This
premise translated into the clinical efficacy of the 5-HT6
receptor antagonist SB-742457 in mild-to-moderate AD patients.
Advances in the understanding of the structure-activity-relationship,
the design of novel 5-HT6
receptor ligands and their potential application for the treatment
of CI are reviewed.
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Phosphodiesterase Inhibitors as Potential Cognition Enhancing
Agents
Christopher J. Schmidt
As might be predicted for an organ designed for cell
to cell communication, cyclic nucleotide signaling in the
brain is highly organized and regulated. Augmentation of cyclic
nucleotide signaling by means of phosphodiesterase inhibition
appears to be a viable and tractable means of enhancing neuronal
communication. Of the various CNS disorders that have been
considered as target indications for phosphodiesterase inhibitors,
no condition has received more attention than cognitive dysfunction.
This review provides a background for understanding the expanding
literature in this field as well as a brief update on the
rationale driving the search for selective inhibitors of targets
such as PDE1B, PDE2, PDE5 and PDE9.
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