Synthesis and structure-activity relationships of a new model of arylpiperazines. 2. Three-dimensional quantitative structure-activity relationships of hydantoin-phenylpiperazine derivatives with affinity for 5-HT1A and alpha 1 receptors. A comparison of CoMFA models

Journal of Medicinal Chemistry
María L López-RodríguezK Schaper

Abstract

A series of 48 bicyclohydantoin-phenylpiperazines (1-4) with affinity for 5-HT1A and alpha 1 receptors was subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis (CoMFA), in order to get insight into the structural requirements that are responsible for 5-HT1A/alpha 1 selectivity. Good models (high cross-validation correlations and predictive power) were obtained for 5-HT1A and alpha 1 receptors. The resulting 3D-QSAR models rationalize steric and electrostatic factors which modulate binding to 5-HT1A and alpha 1 receptors. A comparison of these models gives an additional understanding for 5-HT1A/alpha 1 selectivity: (a) Substitution at the ortho position by a group with negative potential is favorable to affinity for both receptors. (b) The meta position seems to be implicated in 5-HT1A/alpha 1 selectivity. While the 5-HT1A receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the alpha 1 receptor are more restricted (optimum volume of substituent 11-25 A3). (c) For both receptors the para position represents a region where the volume accessible by the ligands is limited. (d) The hydantoin moiety an...Continue Reading

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Citations

Mar 22, 2005·European Journal of Pharmacology·Mercedes DelgadoJosé A Fuentes
Sep 7, 1999·Bioorganic & Medicinal Chemistry Letters·M L López-RodríguezM Murcia
Oct 20, 2012·Chemical Research in Toxicology·Alexey V ZakharovVladimir V Poroikov
Dec 22, 2009·SAR and QSAR in Environmental Research·D A FilimonovV V Poroikov
Mar 18, 2004·Bioorganic & Medicinal Chemistry Letters·Manish TandonMark A Ashwell
Jun 1, 2011·Molecular Informatics·Victor E Kuz'minSergey A Andronati
Jan 13, 2006·Bioorganic & Medicinal Chemistry·Mario V ZlatovićGoran M Roglić
Dec 10, 1999·Journal of Medicinal Chemistry·M H PaluchowskaE Chojnacka-Wójcik
Sep 9, 2010·ACS Medicinal Chemistry Letters·Dulce AlonsoSilvia Ortega-Gutiérrez
Jul 28, 2018·Journal of Agricultural and Food Chemistry·Yuanqiong HuangQingmin Wang

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