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dc.contributor.authorJ. Pratuangdejkulen_US
dc.contributor.authorB. Schneideren_US
dc.contributor.authorP. Jaudonen_US
dc.contributor.authorV. Rosilioen_US
dc.contributor.authorE. Baudoinen_US
dc.contributor.authorS. Loricen_US
dc.contributor.authorM. Contien_US
dc.contributor.authorJ. M. Launayen_US
dc.contributor.authorP. Maniveten_US
dc.contributor.otherHopital Lariboisiere AP-HPen_US
dc.contributor.otherUFR des Sciences Pharmaceutiques et Biologiquesen_US
dc.contributor.otherInstitut Andre Lwoffen_US
dc.contributor.otherUniversite Paris-Sud XIen_US
dc.contributor.otherInstitut Galien Paris-Suden_US
dc.contributor.otherHopital Henri Mondoren_US
dc.contributor.otherHopital de Bicetreen_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherInstitut Pasteur, Parisen_US
dc.identifier.citationCurrent Medicinal Chemistry. Vol.12, No.20 (2005), 2393-2410en_US
dc.description.abstractThe 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.en_US
dc.rightsMahidol Universityen_US
dc.subjectBiochemistry, Genetics and Molecular Biologyen_US
dc.subjectPharmacology, Toxicology and Pharmaceuticsen_US
dc.titleDefinition of an uptake pharmacophore of the serotonin transporter through 3D-QSAR analysisen_US
Appears in Collections:Scopus 2001-2005

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