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

被引:9
作者
SUBRAMANYAM, C
MALLAMO, JP
DORITY, JA
EARLEY, WG
KUMAR, V
AIMONE, LD
AULT, B
MILLER, MS
LUTTINGER, DA
DEHAVENHUDKINS, DL
机构
[1] STERLING WINTHROP PHARMACEUT,DIV RES,DEPT MED CHEM,COLLEGEVILLE,PA 19426
[2] STERLING WINTHROP PHARMACEUT,DIV RES,DEPT PHARMACOL,COLLEGEVILLE,PA 19426
[3] STERLING WINTHROP PHARMACEUT,DIV RES,DEPT BIOCHEM,COLLEGEVILLE,PA 19426
关键词
D O I
10.1021/jm00001a006
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 K-i = 1.8 +/- 0.2 nM vs [H-3]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.
引用
收藏
页码:21 / 27
页数:7
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