Current Pharmaceutical Design, Volume 8, No. 2, 2002
Central Nervous System Agents
A Review of Molecular Modeling Approaches to
Pharmacophore Models and Structure-Activity Relationships of Ion Channel
Modulators in CNS Pp-99-110
Y.
Li and W. E. Harte
Quantitative Structure-Activity Relationship Studies
on Cholecystokinin Antagonists Pp-111-124
Satya
P. Gupta
Design and Study of Piracetam-like
Nootropics,Controversial Members of the Problematic Class of
Cognition-Enhancing Drugs Pp-125-138
Fulvio
Gualtieri, Dina Manetti, Maria Novella Romanelli and Carla Ghelardini
The Potential Utility of 5-HT1A Receptor
Antagonists in the Treatment of Cognitive Dysfunction Associated with
Alzheimer’s Disease Pp-139-145
L.E.
Schechter, L.A. Dawson and J.A. Harder
Analysis of Overall Gene Expression Induced
by Amphetamine and Phencyclidine: Novel Targets for the Treatment of Drug
Psychosis and Schizophrenia Pp-147-153
Chihiro
Ito
[Back to top] A Review of Molecular
Modeling Approaches to Pharmacophore Models and Structure-Activity
Relationships of Ion Channel Modulators in CNS
Y. Li
and W. E. Harte
Through pharmacophore models and providing quantitative analysis of structure-activity relationships (QSAR), molecular modeling techniques can be useful tools to study the interactions of ion channels and their modulators. The present review focuses on molecular modeling approaches that defined pharmacophore models of ion channel modulators in the CNS. The commonality and subtlety of the pharmacophore models of various ion channel modulators are discussed which can be used as a framework for the design of ion channel modulators.
[Back to top] Quantitative
Structure-Activity Relationship Studies on Cholecystokinin Antagonists
Satya
P. Gupta
A
review is presented on quantitative structure-activity relationship (QSAR)
studies on cholecystokinin antagonists. Cholecystokinin (CCK) is a
gastrointestinal peptide hormone closely related chemically to gastrin.
However, its receptors are found in both peripheral and central nervous
systems. Those present in peripheral system have been termed as CCK-A receptors
and those present in central nervous system as CCK-B receptors. QSAR studies
verify that CCK-B receptors are closely related structurally to gastrin
recetors. QSAR studies have been reported on different classes of CCK
antagonists, e.g., benzodiazepine derivatives, amino acid derivatives,
quinazolinones, and peptides and pseudopeptide analogs. These QSAR studies
unravel the mechanisms of interactions of each category of antagonists with the
CCK receptors. In the case of benzodiazepines, the hydrophobic interactions and
hydrogen bondings are found to be the most important binding force, while in
the case of quinazolinones, only the hydrogen bonding is found to be important.
The hydrophobic as well as the dispersion interactions are shown to be
important for the binding of glutamic acid analogs and steric factors appear to
govern the activity of peptides and pseudopeptide analogs.
[Back to top] Design and Study of
Piracetam-like Nootropics, Controversial Members of the Problematic Class of
Cognition-Enhancing Drugs
Fulvio
Gualtieri, Dina Manetti, Maria Novella Romanelli and Carla Ghelardini
Cognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies. Development of cognition enhancers is still a difficult task because of complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. After the early serendipitous discovery of first generation cognition enhancers, current research is based on a variety of working hypotheses, derived from the progress of knowledge in the neurobiopathology of cognitive processes.
Among other classes of drugs, piracetam-like cognition
enhancers (nootropics) have never reached general acceptance, in spite of their
excellent tolerability and safety. In the present review, after a general
discussion of the problems connected with the design and development of
cognition enhancers, the class is examined in more detail. Reasons for the
problems encountered by nootropics, compounds therapeutically available and
those in development, their structure activity relationships and mechanisms of
action are discussed. Recent developments which hopefully will lead to a
revival of the class are reviewed.
[Back to top] The Potential Utility
of 5-HT1A Receptor Antagonists in the Treatment of Cognitive
Dysfunction Associated with Alzheimer’s Disease
L.E.
Schechter, L.A. Dawson and J.A. Harder
The 5-HT1Areceptor has been extensively studied
over the last two decades. There is a plethora of information describing its
anatomical, physiological and biochemical roles in the brain. In addition, the
development of selective pharmacological tools coupled with our understanding
of psychiatric pathology has lead to multiple hypotheses for the therapeutic
utility of 5-HT1A
agents and in particular 5-HT1A receptor antagonists. Over the last decade it has been
suggested that 5-HT1A
receptor antagonists may have therapeutic utility in such diseases as
depression, anxiety, drug and nicotine withdrawal as well as schizophrenia.
However, a very compelling rationale has been developed for the therapeutic
potential of 5-HT1A
receptor antagonists in Alzheimer's disease and potentially other diseases with
associated cognitive dysfunction. Receptor blockade by a 5-HT1A receptor
antagonist appears to enhance activation and signaling through heterosynaptic
neuronal circuits known to be involved in cognitive processes and, as such,
represents a novel therapeutic approach to the treatment of cognitive deficits
associated with Alzheimer's disease and potentially other disorders with
underlying cognitive dysfunction.
[Back to
top] Analysis
of Overall Gene Expression Induced byAmphetamine and Phencyclidine: Novel
Targets for the Treatment of Drug Psychosis and Schizophrenia
Chihiro
Ito
Although the etiology of drug psychosis or schizophrenia
is still unknown, molecular and biochemical researches have recently made
significant advances in the search for the candidate genes of these disorders. Among
such studies are animal models of drug psychosis or schizophrenia such as
amphetamine-induced behavioral sensitization or phencyclidine-treated animals.
In this review, it is suggested that amphetamine or phencyclidine change the
gene expressions related to not only neurotransmistter systems such as dopamine
or glutamic acid, transcription factors, cell proliferation, apoptosis, cell
adhesion, but also the synapse. These alterable gene expressions may lead to
the discovery of candidate genes of drug psychosis or schizophrenia and thus to
novel antipsychotics.