188915-10-8Relevant articles and documents
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- HT(1A) and α1 receptors. A comparison of CoMFA models
López-Rodríguez, María L.,Rosado, Ma. Luisa,Benhamú, Bellinda,Morcillo, Ma. José,Fernández, Esther,Schaper, Klaus-Jürgen
, p. 1648 - 1656 (1997)
A series of 48 bicyclohydantoin-phenylpiperazines (1-4) with affinity for 5-HT(1A) and α1 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-HT(1A)/α1 selectivity. Good models (high cross-validation correlations and predictive power) were obtained for 5-HT(1A) and α1 receptors. The resulting 3D-QSAR models rationalize steric and electrostatic factors which modulate binding to 5-HT(1A) and α1 receptors. A comparison of these models gives an additional understanding for 5-HT(1A)/α1 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-HT(1A)/α1 selectivity. While the 5-HT(1A) receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the α1 receptor are more restricted (optimum volume of substituent 11-25 A?3). (c) For both receptors the para position represents a region where the volume accessible by the ligands is limited. (d) The hydantoin moiety and the side chain length seem to modulate not only the affinity but also 5-HT(1A)/α1 selectivity. The 3D- QSAR models reveal an useful predictive information for the design of new selective ligands.
