| Recent
Patents on CNS Drug Discovery
ISSN: 1574-8898
Recent Patents on CNS Drug
Discovery
Volume 1, Number 1, June 2006
Contents
Non-Monoamine-Based Approach for the Treatment
of Depression and Anxiety Disorders Pp.1-27
Shigeyuki Chaki, Taketoshi Okubo & Yoshinori Sekiguchi
[Abstract]
[Full
Text Article]
Tianeptine: A Novel Atypical Antidepressant that
May Provide New Insights into the Biomolecular Basis of Depression
Pp.29-41
Christiaan B. Brink, Brian H. Harvey & Linda Brand
[Abstract] [Full
Text Article]
Glycine Transporter Inhibitors as Therapeutic
Agents for Schizophrenia Pp.43-53
Kenji Hashimoto
[Abstract] [Full
Text Article]
The Quest to Repair the Damaged Spinal Cord
Pp.55-63
Maria Teresa Moreno-Flores & Jesús Ávila
[Abstract] [Full
Text Article]
TRPV1 Antagonists as a Potential Treatment for
Hyperalgesia Pp.65-76
Louise A Roberts & Mark Connor
[Abstract] [Full
Text Article]
Miglustat: Substrate Reduction Therapy for Lysosomal
Storage Disorders Associated with Primary Central Nervous
System Involvement Pp.77-82
Gregory M. Pastores
[Abstract] [Full
Text Article]
Voltage-Gated Sodium Channel Blockers as Immunomodulators
Pp.83-91
Francesco Roselli, Paolo Livrea & Emilio Jirillo
[Abstract] [Full
Text Article]
The Astrocytic GABAA/Benzodiazepine-Like
Receptor: The Joker Receptor for Benzodiazepine-Mimetic Drugs?
Pp.93-103
Leif Hertz, Zhong Zhao & Ye Chen
[Abstract] [Full
Text Article]
Galanthamine, a Natural Product for the Treatment
of Alzheimer’s Disease Pp.105-111
Luis Marco & Maria do Carmo Carreiras
[Abstract] [Full
Text Article]
An Update on GABA Analogs for CNS Drug Discovery
Pp.113-118
Perumal Yogeeswari, Jegadeesan Vaigunda Ragavendran &
Dharmarajan Sriram
[Abstract] [Full
Text Article]
Therapeutic Perspectives in Alzheimer's disease
Pp.119-127
Jakob-A. Tschäpe & Tobias Hartmann
[Abstract] [Full
Text Article]
Patent
Annotations Pp.129-132
Patent
Selections Pp.133-138
Abstracts
[Back to top]
Non-Monoamine-Based Approach for the Treatment of
Depression and Anxiety Disorders
Shigeyuki Chaki, Taketoshi Okubo & Yoshinori Sekiguchi
[Full Text Article]
Although currently prescribed antidepressants with actions
mediated through alteration of monoaminergic transmission
have been proven to be useful for the treatment of depressive
and anxiety disorders, they are far from ideal due to their
slow onset of action and low rate of responses. Although the
brain monoamine systems have long been the focus of drug therapy
for depression and anxiety disorders, current drug discovery
has aimed at new molecular targets outside the monoamine systems
to overcome these problems. Recent increase in understanding
of the molecular mechanisms of depression and anxiety has
provided alternative molecular targets for these disorders.
In particular, receptors within the glutamate, γ-aminobutyric
acid and neuropeptide systems provide a diversity of drug
targets, and molecular biological and behavioral studies of
these receptors have revealed the important roles they play
in depression and anxiety. Here, we review recent patents
and advances in research on these emerging molecular targets
for the treatment of depression and anxiety, and discuss their
advantages over currently used antidepressants and anxiolytics.
[Back to top]
Tianeptine: A Novel Atypical Antidepressant that May
Provide New Insights into the Biomolecular Basis of Depression
Christiaan B. Brink, Brian H. Harvey & Linda Brand
[Full
Text Article]
Tianeptine, an atypical antidepressant patented and developed
by Servier, enhances the synaptic reuptake of serotonin, without
affecting norepinephrine and dopamine uptake, while it lacks
affinity for neurotransmitter receptors. This mechanism for
an antidepressant is apparently paradoxical, since the currently
employed antidepressants enhance serotonin by inhibiting its
breakdown or by inhibiting monoaminergic reuptake. Although
tianeptine has been shown to reduce central 5HT availability
and to indirecty modulate central adrenergic and dopaminergic
systems and to indirectly inhibit cholinergic hyperactivity,
its antidepressant action is believed to be more directly
related to central neuronal remodeling and restoration of
neuronal plasticity. In reliable animal models of depression
tianeptine has been shown to prevent neurodegeneration and
decreases in hippocampal volume in response to chronic stress.
These effects on neuroplasticity are suspected to involve
the normalization of the hypothalamic-pituitary-adrenal axis
and modulatory effects on excitatory amino acids and N-methyl-D-aspartate
receptors. Together with a body of related studies, these
data provide further support for the hypothesis that depression
may involve dysregulation of pathways controlling cellular
resilience and that treatment should be directed towards the
reversal thereof. Importantly, tianeptine is not anxiogenic
and has also been shown to be effective in treatment-resistant
depression, which may lead the way to a major breakthrough
in the treatment of depression.
[Back to top]
Glycine Transporter Inhibitors as Therapeutic Agents
for Schizophrenia
Kenji Hashimoto
[Full Text Article]
Multiple lines of evidence suggest that a dysfunction in
the glutamatergic neurotransmission via the N-methyl-D-aspartate
(NMDA) receptors contributes to the pathophysiology of psychiatric
diseases including schizophrenia. The potentiation of NMDA
receptor function may be a useful approach for the treatment
of diseases associated with NMDA receptor hypofunction. One
possible strategy is to increase synaptic levels of glycine
by blocking the glycine transporter-1 (GlyT-1) in glia cells,
since glycine acts as a co-agonist site on the NMDA receptor.
In this article, the author reviews the recent important patents
on GlyT-1 inhibitors for treatment of schizophrenia and other
psychiatric diseases associated with the NMDA receptor hypofunction.
[Back to top]
The Quest to Repair the Damaged Spinal Cord
Maria Teresa Moreno-Flores & Jesús Ávila
[Full Text Article]
Spinal cord injuries devastate the lives of those affected.
Normally, acute injury leads to chronic injury in the spinal
cord, although this has a variable impact on normal sensory
and motor functions. Currently the only drug used to treat
acute spinal cord injury is methyl-prednisolone, administered
in order to prevent secondary inflammatory neural damage.
Thus, it is time that alternative and complementary pharmacological,
cell and gene therapies be developed. In order to achieve
this, several approaches to stimulate spinal cord repair must
be considered. Indeed, the main lines of research that have
been established in different animal models of spinal cord
regeneration are now beginning to produce encouraging results.
Several patents have been derived from these studies and hopefully,
they will lead to the development of new treatments for human
spinal cord injuries. Here is presented a review of the main
patents that have been generated by this research, and that
can be classified as:
- Patents involving the use of different factors that promote
axonal regeneration.
- Patents aimed at overcoming the activity of glial scar
inhibitory molecules that hinder axonal regeneration. These
approaches can be further subdivided into those that block
Nogo and other myelin components, and those that involve the
use of chondroitinase against glial scar chondroitin sulphate
proteoglycans.
- Patents concerning glial cell therapy, in which glial cells
are used to mediate axonal repair in the spinal cord (Schwann
cells, olfactory ensheathing cells or astrocytes).
[Back to top]
TRPV1 Antagonists as a Potential Treatment for Hyperalgesia
Louise A Roberts & Mark Connor
[Full Text Article]
The vanilloid receptor (TRPV1) is a member of the transient
receptor potential family of ion channels that is highly expressed
in nociceptive primary afferent sensory neurons. TRPV1 is
a voltage-dependent cation channel, which can be activated
at physiological membrane potentials by stimuli including
noxious heat (>42 degrees), capsaicin, hydrogen ions and
anandamide. Activation of TRPV1 results in release of neurotransmitters
from peripheral and central nerve terminals resulting in pain
and inflammation. Endogenous inflammatory mediators also promote
activation of TRPV1. Studies in TRPV1 null mice reveal that
responses to noxious heat stimuli are normal but the development
of thermal hyperalgesia is abolished. Several TRPV1 antagonists
have recently been developed and reported to alleviate or
reverse mechanical and thermal hyperalgesia associated with
inflammatory pain. This review will examine the development
of patented TRPV1 antagonists as a potential clinical treatment
for the alleviation of pain associated with hyperalgesia and
inflammation.
[Back to top]
Miglustat: Substrate Reduction Therapy for Lysosomal
Storage Disorders Associated with Primary Central Nervous
System Involvement
Gregory M. Pastores
[Full Text Article]
Difficulties with delivery of functional enzyme to the brain
limit the ability to modify neurologic outcome in patients
with neuronopathic forms of the lysosomal storage diseases.
In a subset of these disorders, which result from a disruption
of glycosphingolipid metabolism, the use of a small molecule
inhibitor of substrate precursor synthesis may reduce the
amount of brain tissue lipid deposition and lead to amelioration
of disease. The efficacy of this approach, termed substrate
reduction therapy, has been demonstrated in several animal
models; with resultant reduction of ganglioside storage in
the brain, delayed onset of symptoms and prolonged survival.
This pre-clinical ‘proof of therapeutic concept’
served as the rationale for proceeding with trials in humans
using miglustat; an imino-sugar inhibitor of ceramide-specific
glucosytransferase (the catalyst for the first committed step
in glycosphingolipid synthesis). The glycosphingolipidoses
are rare ‘orphan’ disorders; the limited number
of suitable study subjects and the paucity of information
on the natural history of these disorders represent major
hurdles in the conduct of clinical trials. As treatment potentially
constitutes lifelong administration, there will be a need
to identify any potential safety considerations attendant
to the use of these agents. With greater understanding of
disease mechanism, adjunctive therapies may be identified;
offering the prospect of modifying these otherwise relentlessly
progressive neurodegenerative diseases.
[Back to top]
Voltage-Gated Sodium Channel Blockers as Immunomodulators
Francesco Roselli, Paolo Livrea & Emilio Jirillo
[Full Text Article]
Several Voltage-Gated Sodium Channels (VGSC) are widely expressed
on lymphocytes and macrophages but their role in immune function
is still debated. Nevertheless, Na+ influx through VGSC is
required for lymphocytes activation and proliferation, since
these responses are blocked by Na+-free medium or by VGSC
blockers. These effects may be mediated by the reduced intracellular
Na+ levels, which in turn may impair the activity
of Na+/Ca++ exchanger resulting in reduced
intracellular Ca++ levels during lymphocyte activation.
Furthermore, in Jurkat cell line VGSC appear to be involved
in cell volume regulation, migration in artificial matrix
and cell death by apoptosis. VGSC play a role in macrophage
function as well, and VGSC blockers impair both phagocytosis
and inflammatory responses. Several VGSC blockers have shown
immunomodulatory properties in mice models, skewing the immune
response toward a Th2-mediated response, while suppressing
Th1-mediated responses, and VGSC already used in clinical
practice are known to modulate immunoglobulin (Ig) levels
both in mice and in humans. These effects suggest that VGSC
blockers may find clinical application in the treatment of
autoimmune and inflammatory disease. However, many of these
drugs induce a number of severe side effects. The relevance
of VGSC function in immune regulation suggest that the testing
of newly patented VGSC blockers for their effect on immunity
may be worthwhile.
[Back to top]
The Astrocytic GABAA/Benzodiazepine-Like Receptor:
The Joker Receptor for Benzodiazepine-Mimetic Drugs?
Leif Hertz, Zhong Zhao & Ye Chen
[Full Text Article]
Long-term use of benzodiazepines as hypnotics, anxiolytics,
anticonvulsants and muscle relaxing drugs is jeopardized by
adverse effects on memory, addictive properties, and development
of tolerance. Major efforts have gone into developing 'benzodiazepine-like'
drugs that are more selective in their therapeutic effect,
have additional uses and/or lack the adverse effects of benzodiazepines.
The reviewed prototype patent exemplifies such efforts. Newer
drugs are thought to act selectively on one of the two neuronal
benzodiazepine receptors, on the astrocytic mitochondrial
benzodiazepine receptor and/or on GABAA/benzodiazepine
receptor complexes displaying specific subunits. It is overlooked
that astrocytes also express benzodiazepine receptors that
enhance depolarization-mediated entry of Ca2+ by
interacting with membrane-associated GABAA-like
receptors, mediating depolarization because of a
high Cl- concentration within astrocytes. The resulting increase
in free cytosolic Ca2+, which stimulates glycogenolysis,
is inhibited not only by the 'peripheral-type' benzodiazepine
antagonist PK11195 but also by the 'neuronal' antagonist flumazenil.
Increasing awareness of the role(s) of astrocytic Ca2+
homeostasis and energy metabolism for CNS function suggests
that activation of this receptor might contribute to both
therapeutic and adverse effects of benzodiazepine-like drugs.
This receptor should be kept in mind when developing and testing
new drugs; in turn these drugs may help elucidating its functional
role.
[Back to top]
Galanthamine, a Natural Product for the Treatment
of Alzheimer’s Disease
Luis Marco & Maria do Carmo Carreiras
[Full Text Article]
(-)-Galanthamine is a selective, reversible competitive acetylcholinesterase
inhibitor that has been recently approved for the symptomatic
treatment of Alzheimer’s disease. Galanthamine is a
natural product belonging to the Amaryllidaceae family
of alkaloids. The pharmacological history of galanthamine
shows that the bioactive compound was discovered accidentally
in the early 1950s, and the plant extracts were initially
used to treat nerve pain and poliomyelitis. In addition, galanthamine
had since been tested for use in anesthesiology, from facial
nerve paralysis to schizophrenia. Galanthamine is a long-acting,
selective, reversible and competitive AChE inhibitor that
has recently been tested in AD patients and found to be readily
absorbed, to be a performance enhancer on memory tests in
some patients, and to be well tolerated, although some cholinergic
side effects were observed. A number of total synthetic approaches
have been reported, and a method for the industrial scale-up
preparation of galanthamine is now being developed and patented.
A variety of galanthamine derivatives have also been synthesized
aiming to develop an agent free from cholinergic adverse effects.
Galanthamine is a natural product that complements other synthetic
drugs for the management of AD. In this account we will review
the Recent Patent literature showing the most important advance
on the chemistry of galanthamine.
[Back to top]
An Update on GABA Analogs for CNS Drug Discovery
Perumal Yogeeswari, Jegadeesan Vaigunda Ragavendran &
Dharmarajan Sriram
[Full Text Article]
GABA (γ-aminobutyric
acid) is one of the major inhibitory transmitters in the central
nervous system of mammals. GABA is not transported efficiently
into the brain from the bloodstream (i.e. GABA does not effectively
cross the blood-brain barrier). Consequently, brain cells
provide virtually all of the GABA found in the brain i.e.
GABA is biosynthesized by decarboxylation of glutamic acid
with pyridoxal phosphate. The implication of low GABA levels
in a number of common CNS disease states and/or common medical
disorders has stimulated intensive interest in preparing GABA
analogs, which have superior pharmaceutical properties in
comparison to GABA. Accordingly, a number of GABA analogs,
with considerable pharmaceutical activity have been synthesized
in the art. This review includes some of the important recent
patents on novel GABA analogues and some pharmaceutical compositions
there of.
[Back to top]
Therapeutic Perspectives in Alzheimer's disease
Jakob-A. Tschäpe & Tobias Hartmann
[Full Text Article]
It is now almost a century ago that Alois Alzheimer first
presented his results in public. Main characteristics of Alzheimer’s
disease (AD) are massive cerebral accumulation of amyloid,
composed of fibrillary aggregates of the Amyloid beta peptide
(Aß) and intracellular accumulation of abnormally phosphorylated
tau protein associated with widespread neurodegeneration.
The clinical picture is characterized by progressive and irreversible
dementia, which is eventually fatal. To date, there is no
cure for this severe disease affecting upwards of 30 millions
individuals worldwide. In the last decades, the treatment
of Alzheimer patients was mainly focusing on symptomatical
strategies. Based on the augmented knowledge about the mechanisms
underlying the pathology of AD, particularly the molecular
causes and consequences of AD, different therapeutic approaches
arose and recently treatment with Statins, NSAIDs and Aß
vaccines reached the level of clinical trials, showing some
indication of efficacy already. According to actual evaluations,
these approaches have realistic chances to become established
as therapeutic routine in AD within the next 10 years. We
will review here some of the most promising novel approaches
to cure and prevent rather than to treat the symptoms of AD.
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