188915-12-0Relevant articles and documents
Design and synthesis of 2-[4-[4-(m-(ethylsulfonamido)-phenyl)piperazin- 1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2c]imidazole (EF-7412) using neural networks. A selective derivative with mixed 5-HT(1A)/D2 antagonist properties
Lopez-Rodriguez, Maria L.,Morcillo, M. Jose,Fernandez, Esther,Rosado, M. Luisa,Orensanz, Luis,Beneytez, M. Eugenia,Manzanares, Jorge,Fuentes, Jose A.,Schaper, Klaus-Juergen
, p. 1679 - 1682 (1999)
A test series of 32 phenylpiporazines III with affinity for 5-HT(1A) and α1 receptors was subjected to QSAR analysis using artificial neural networks (ANNs), in order to get insight into the structural requirements that are responsible for 5-HT(1A)/α1 selectivity. Good models and predictive power were obtained for 5-HT(1A) and α1 receptors. A comparison of these models gives information for the design of the new ligand EF-7412 (5-HT(1A):K(i) (nM)= 27; α1 (nM) > 1000). This derivative displayed affinity for dopamine D2 receptor (K(i)= 22 nM) and is selective for all other receptor examined (5-HT(2A), 5-HT3, 5-HT4 and Bz). EF-7412 acts an antagonist in vivo in pre-and postsynaptic 5-HT(1A) receptor sites and as an antagonist in dopamine D2 receptor.
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 (2007/10/03)
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.
