RESUMO
A unique combination of alpha 2-adrenoreceptor antagonist and serotonin-selective reuptake inhibitory activities has been identified in a series of 2-substituted 4,5-dihydro-1H-imidazole derivatives. This combination of blocking activities has provided one of these derivatives, napamezole hydrochloride (2), with potential as an antidepressant. A discussion of the syntheses of these compounds includes a convenient method for the conversion of nitriles to imidazolines with ethylenediamine and trimethylaluminum.
Assuntos
Antidepressivos , Imidazóis/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Serotonina/metabolismo , Animais , Blefaroptose/induzido quimicamente , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Químicos , Química , Dioxanos/metabolismo , Dioxanos/farmacologia , Dopamina/metabolismo , Idazoxano , Imidazóis/síntese química , Imidazóis/metabolismo , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/fisiologia , Relação Estrutura-Atividade , Tetrabenazina/antagonistas & inibidores , p-Cloroanfetamina/antagonistas & inibidoresRESUMO
6,11-Ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations 8, a novel class of N-methyl-D-aspartate (NMDA) antagonists acting at the phencyclidine site, have been identified. Structure-activity relationship studies around the lead compound 8a led to the identification of 12g (WIN 67870-2), one of the most potent compounds in this series. Compound 12g has a Ki = 1.8 +/- 0.2 nM vs [3H]TCP binding, has 700-fold selectivity for binding to the open state of the NMDA receptor-ionophore, and was devoid of MK-801- and PCP-like behavioral effects in rats. Compound 12g was neuroprotective in cultured mouse cortical neurons and exhibited antiischemic activity in a rat middle cerebral artery occlusion/reperfusion model of focal ischemia.