title: 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.
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 and the side chain length seem to modulate not only the affinity but also 5-HT1A/alpha 1 selectivity. The 3D-QSAR models reveal an useful predictive information for the design of new selective ligands.
authors.affiliation: Departmento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain.
authors.forename: M L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: M L
authors.initials: ML
authors.lastname: Rosado
authors.forename: B
authors.initials: B
authors.lastname: Benhamú
authors.forename: M J
authors.initials: MJ
authors.lastname: Morcillo
authors.forename: E
authors.initials: E
authors.lastname: Fernández
authors.forename: K J
authors.initials: KJ
authors.lastname: Schaper
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004563:Electrochemistry; D006827:Hydantoins / Q000138:chemical synthesis*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D006827:Hydantoins; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; C031503:phenylpiperazine