RESUMO
We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 1 , Piperazinas/síntese química , Pirazinas/síntese química , Agonistas do Receptor 5-HT1 de Serotonina , Adenilil Ciclases/biossíntese , Sequência de Aminoácidos , Animais , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Simulação por Computador , Reação de Fuga/efeitos dos fármacos , Células HeLa , Humanos , Técnicas In Vitro , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Piperazinas/química , Piperazinas/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Alinhamento de Sequência , EstereoisomerismoRESUMO
A series of new benzimidazole-arylpiperazine derivatives III were designed, synthesized and evaluated for binding affinity at serotoninergic 5-HT(1A) and 5-HT(3) receptors. Compound IIIc was identified as a novel mixed 5-HT(1A)/5-HT(3) ligand with high affinity for both serotonin receptors and excellent selectivity over alpha(1)-adrenergic and dopamine D(2) receptors. This compound was characterized as a partial agonist at 5-HT(1A)Rs and a 5-HT(3)R antagonist, and was effective in preventing the cognitive deficits induced by muscarinic receptor blockade in a passive avoidance learning test.
