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Title: Definition of an uptake pharmacophore of the serotonin transporter through 3D-QSAR analysis
Authors: J. Pratuangdejkul
B. Schneider
P. Jaudon
V. Rosilio
E. Baudoin
S. Loric
M. Conti
J. M. Launay
P. Manivet
Hopital Lariboisiere AP-HP
UFR des Sciences Pharmaceutiques et Biologiques
Institut Andre Lwoff
Universite Paris-Sud XI
Institut Galien Paris-Sud
Hopital Henri Mondor
Hopital de Bicetre
Mahidol University
Institut Pasteur, Paris
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 23-Sep-2005
Citation: Current Medicinal Chemistry. Vol.12, No.20 (2005), 2393-2410
Abstract: The serotonergic system plays a critical role in a wide variety of physiological and behavioral processes. Dysregulation of the tightly controlled extracellular concentration of serotonin (5-hydroxytryptamine, 5-HT) appears to be at the origin of a host of metabolic and psychiatric disorders. Since the plasma membrane 5-HT transporter (SERT) is the major protagonist in regulating extracellular 5-HT concentration, SERT is the target of most drugs interacting with the serotonergic system. Unfortunately, some of the drugs towards SERT (e.g. amphetamine derivatives) interfere with cell homeostasis leading to cell toxicity. Developing new SERT ligands devoid of any side-effect represents a major priority in the treatment of 5-HT-associated pathologies. Here, we report structure-activity relationships (SAR) and three-dimensional QSAR (3D-QSAR) studies of a library of 121 compounds including 5-HT analogs, harmanes, benzothiazoles, indanones, amphetamine derivatives and substrate-type 5-HT releasers, with the goal of identifying the structural determinants crucial for SERT uptake. In the absence of data about the bioactive form of 5-HT, conformational analysis of 5-HT was performed using quantum chemistry calculations. This led to three 5-HT stable conformers with anti, -gauche and +gauche side-chain conformation. These conformers, used as templates for superimposition with all the library compounds, enabled the design of a reliable 6-points pharmacophore representative of SERT uptake activity. Molecular dynamics (MD) simulations performed with compounds that are efficiently, moderately, poorly or not transported by SERT allowed to assess the validity of our pharmacophore. Altogether, our data provide for the first time a reliable pharmacophore of SERT uptake activity, which may help to the design of new drugs targeting SERT. © 2005 Bentham Science Publishers Ltd.
ISSN: 09298673
Appears in Collections:Scopus 2001-2005

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