Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 6, Number 2, June 2006
Contents
Dysiherbaine: A New Generation of Excitatory Amino
Acids of Marine Origin Pp. 83-108
Ryuichi Sakai, Geoffrey T. Swanson, Makoto Sasaki, Keiko
Shimamoto and Hisao Kamiya
[Abstract]
Targeting Stress Activated Protein Kinases, JNK and
p38, as New Therapeutic Approach for Neurodegenerative Diseases
Pp. 109-117
Caterina Bendotti, Massimo Tortarolo and Tiziana Borsello
[Abstract]
Potassium Channels as Targets for the Management of
Pain Pp. 119-128
Kim Lawson
[Abstract]
Platelet-Activating Factor (PAF) Antagonists Attenuate
Inflammatory-Based Pain: Potential Cellular and Anatomical
Sites of PAF Action Pp. 129-133
Lisa A. Teather
[Abstract]
Augmentation Strategies to Improve Treatment of Major
Depression Pp. 135-152
Minke E. Jongsma, M.C.G. van der Hart, Joanna I. Udo de
Haes, Thomas I.F.H. Cremers, Ben H.C. Westerink, Johan A.
den Boer and Fokko J. Bosker
[Abstract]
Abstracts
[Back to top]
Dysiherbaine: A New Generation of Excitatory Amino
Acids of Marine Origin
Ryuichi Sakai, Geoffrey T. Swanson, Makoto Sasaki, Keiko
Shimamoto and Hisao Kamiya
The molecular diversity of marine secondary metabolites
has been recognized for a number of years, and classic marine-derived
excitatory amino acids (EAAs) such as kainic and domoic acid
have been indispensable tools in neurobiological research.
The recent discovery of the sponge-derived EAA dysiherbaine
(DH, 1), a novel di-amino di-acid glutamate analogue with
potent convulsant activity, underscores the relatively untapped
potential of marine organisms to serve as sources of EAAs
with unique structures and activities [1]. DH (1) has a number
of pharmacological actions but binds with highest affinity
to kainate receptors, a sub-family of non-N-methyl-D-aspartate
(non-NMDA)-type GluRs, which are also the molecular targets
of other potent EAA convulsants like domoic acid. The high
affinity and selectivity of 1 towards certain kainate receptor
subtypes made it a useful tool for exploring aspects of the
biophysical function of these ion channels [2].
In combination with chemical syntheses and neurophysiological
techniques, we have shown that 1 and its structural analogues
can serve as unique biophysical and physiological probes of
GluR function [3]. Current studies have begun to elucidate
the critical moieties on 1 that confer activity and selectivity.
We anticipate that 1 will serve as a useful template upon
which to build molecules with novel pharmacological actions
and potential therapeutic applications. In this review, we
describe the chemical, pharmacological and behavioral profile
of 1 and closely related analogues, with a particular emphasis
on their actions on iGluRs, a family of ligand-gated ion channel
critical for excitatory neurotransmission in the mammalian
brain.
[Back to top]
Targeting Stress Activated Protein Kinases,
JNK and p38, as New Therapeutic Approach for Neurodegenerative
Diseases
Caterina Bendotti, Massimo Tortarolo and Tiziana Borsello
Signal transduction pathways involving the activation of
c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein
kinase (p38MAPK), also called stress-activated protein kinases,
have been implicated in many cellular processes such as proliferation,
differentiation and death of a variety of cell populations.
Growing evidence indicates that these pathways can strongly
contribute to the neuronal death associated to neurodegenerative
diseases such as Alzheimer’s, Parkinson’s, amyotrophic
lateral sclerosis and cerebral ischemia . These kinases can
be activated by a variety of toxic stimuli such as oxidative
stress, excitotoxicity, inflammatory cytokines through different
signalling cascades. Once activated these kinase cascades
may induce alterations in the cellular function through transcriptional
activity, alterations of cytoskeletal proteins and production
and release of inflammatory molecules, all factors highly
implicated in the neurodegenerative processes.
Thus considerable effort is being addressed to the manipulation
of these signal transduction pathways as a potential strategy
for therapeutic interventions in neurodegenerative disorders.
In this review we will examine the role of JNK and p38MAPK
in neurodegeneration and we will illustrate the progresses
in the development of inhibitors targeting these stress activated
protein kinase pathways as therapeutic approach to neurodegenerative
disorders.
[Back to top]
Potassium Channels as Targets for the Management of
Pain
Kim Lawson
Potassium (K+) channels play a critical role
in regulating neuronal excitability, a fundamental feature
of pain. The opening of K+ channels leads to hyperpolarization
of the cell membrane, which results in a decrease of cell
excitability. In the nociceptive pathways, K+ channels
are involved in a number of processes within the nervous system,
including neuronal depolarization, axonal conduction, and
neurotransmitter release. As a consequence of the role played
by K+ channels in the regulation of the nociceptive
system and that K+ channel opening is involved
in the antinociception induced by numerous analgesic drugs
they have begun to be considered as direct targets for the
development of new antinociceptive therapies. A limited number
of potential K+ channels have, so far, been identified
as targets for the development of antinociceptive therapies.
This review considers the potential of selective modulators
of KCNQ, KATP,
GIRK, Two-pore domain K+ channels, or KCa
channels as novel therapeutic approaches to pain. Structure-activity
relationship (SAR) studies to identify K+ channel
selective modulators to target neuroexcitability and pain
have, however, been limited to modulators KCNQ channels. The
scope of the field of K+ channel modulators is
just emerging but demonstrates promise for novel therapeutics
in the management of pain.
[Back to top]
Platelet-Activating Factor (PAF) Antagonists Attenuate
Inflammatory-Based Pain: Potential Cellular and Anatomical
Sites of PAF Action
Lisa A. Teather
Platelet-activating factor (PAF) is a phospholipid mediator
with widespread biological actions. PAF acts as both an intercellular
and intracellular mediator via activation of plasma membrane
and intracellular binding sites, respectively. Pharmacological
manipulations – using cell site-specific PAF antagonists
- can be used to dissect the site of PAF action. Evidence
suggests that PAF is a mediator of inflammatory-based pain;
PAF elicits, and PAF antagonists attenuate, the inflammatory
nociceptive response. For instance, using the biphasic formalin
model in rats, we recently demonstrated that systemic, cerebral,
and hippocampal administration of PAF antagonists - selective
for either intracellular or plasma membrane PAF receptors
- decreased the late-phase of the nociceptive response. Interestingly,
the site-selective PAF antagonists may act at distinct anatomical
locations to alleviate nociception. Thus, PAF may not only
at act at distinct anatatomical sites, but at distinct binding
sites within these anatomical locales, to modulate the processing
of pain of an inflammatory nature. PAF is known to elicit
rapid activation of several protein kinase pathways, and to
induce mobilization of prostaglandin E2
(PGE2)
release. As these mediators are critical signals in nociception,
PAF could be an important early mediator of inflammatory-based
pain.
[Back to top]
Augmentation Strategies to Improve Treatment of Major
Depression
Minke E. Jongsma, M.C.G. van der Hart, Joanna I. Udo de
Haes, Thomas I.F.H. Cremers, Ben H.C. Westerink, Johan A.
den Boer and Fokko J. Bosker
The monoamine hypothesis has dominated almost forty years
the psychopathology of depression. Yet this has not lead to
antidepressants that are significantly more efficacious than
the early tri- and tetracyclics from which they have evolved.
Alternative hypotheses such as those involving adult neurogenesis
or components of the hypothalamic-pituitary-adrenal-axis are
either too premature or have not lead to drugs with improved
antidepressant activity. Antidepressants may not be perfect,
both in terms of efficacy and side effects, however their
performance may be improved by making use of so-called augmentation
strategies. Augmentation strategies that have potential to
hasten and/or improve the therapeutic effect of antidepressants,
in particular serotonin reuptake inhibitors, can have different
forms. They can be aimed at reducing comorbid symptoms, such
as anxiety, or they may be directed to processes that counteract
the effect of serotonin reuptake inhibitors. Examples of the
latter are those involving 5-HT1A
and 5-HT1B
autoreceptors, 5-HT2C
receptors and the availability of tryptophan. Another option
could be exploring neuropeptide/serotonin interactions. The
various augmentation strategies are reviewed in the context
of literature data regarding neurobiology and pharmacotherapy
of major depression.
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