RESUMO
A structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channel blockers that were highly selective over L-type calcium channel blockers. Among the tested compounds, (+)-4-(3,5-dichloro-4-methoxy-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-cinnamyl ester was found to be an effective and selective N-type calcium channel blocker with oral analgesic potential.
Assuntos
Analgésicos/química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/química , Ácidos Carboxílicos/química , Di-Hidropiridinas/química , Administração Oral , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Formaldeído/toxicidade , Medição da Dor/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Antiallergic drug cyproheptadine (Cyp) is known to have inhibitory activities for L-type calcium channels in addition to histamine and serotonin receptors. Since we found that Cyp had an inhibitory activity against N-type calcium channel, Cyp was optimized to obtain more selective N-type calcium channel blocker with analgesic action. As a consequence of the optimization, we found 13 with potent N-type calcium channel inhibitory activity which had lower inhibitory activities against L-type calcium channel, histamine (H1), and serotonin (5-HT2A) receptors than those of Cyp. 13 showed an oral analgesic activity in rat formalin-induced pain model.