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.
J Med Chem
; 40(11): 1648-56, 1997 May 23.
Article
en En
| MEDLINE
| ID: mdl-9171874
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Modelos Moleculares
/
Receptores de Serotonina
/
Receptores Adrenérgicos alfa
/
Hidantoínas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1997
Tipo del documento:
Article
País de afiliación:
España