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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1995年 / 38卷 / 01期

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

页码：21 / 27

页数：7

共 28 条

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