RESUMO
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.
Assuntos
Compostos de Quinolínio/síntese química , Compostos de Quinolínio/farmacologia , Quinolizinas/síntese química , Quinolizinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Sítios de Ligação , Isquemia Encefálica/tratamento farmacológico , Cátions , Eletrofisiologia , Fenciclidina/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
