DISCOVERY OF ANO-12,12-DIARYL-6,11-DIHYDROBENZO[B]QUINOLIZINIUM CATIONS, A NOVEL CLASS OF N-METHYL-D-ASPARTATE ANTAGONISTS

ano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations 8, a novel class of N-methyl-D-aspartate (NMDA) antagonists acting at the phencyc lidine site, have been identified. Structure-activity relationship stu dies around the lead compound 8a led to the identification of 12g (WIN 67870-2), one of the most potent compounds in this series. Compound 1 2g has a K-i = 1.8 +/- 0.2 nM vs [H-3]TCP binding, has 700-fold select ivity for binding to the open state of the NMDA receptor-ionophore, an d was devoid of MK-801- and PCP-like behavioral effects in rats. Compo und 12g was neuroprotective in cultured mouse cortical neurons and exh ibited antiischemic activity in a rat middle cerebral artery occlusion /reperfusion model of focal ischemia.