Identification of a novel, selective GABAA α5 receptor inverse agonist which enhances cognition

被引：129

作者：

Chambers, MS ^{[1
]}

Atack, JR ^{[1
]}

Broughton, HB ^{[1
]}

Collinson, N ^{[1
]}

Cook, S ^{[1
]}

Dawson, GR ^{[1
]}

Hobbs, SC ^{[1
]}

Marshall, G ^{[1
]}

Maubach, KA ^{[1
]}

Pillai, GV ^{[1
]}

Reeve, AJ ^{[1
]}

MacLeod, AM ^{[1
]}

机构：

[1] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2003年 / 46卷 / 11期

关键词：

D O I：

10.1021/jm020582q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In pursuit of a GABA(A) alpha5-subtype-selective inverse agonist to enhance cognition, a series of 6,7-dihydro-2-benzothiophen-4(5H)-ones has been identified as a novel class of GABAA receptor ligands. These thiophenes have higher binding affinity for the GABA(A) alpha(5) receptor subtype compared to the GABA(A) alpha(1), alpha(2), and alpha(3) subtypes, and several analogues exhibit high GABA(A) (alpha(5) receptor inverse agonism. 6,6-Dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro2-benzothiophen-4(5H)-one (43) has been identified as a full inverse agonist at the GABA(A) alpha5 receptor and is functionally selective over the other major GABA(A) receptor subtypes. 43 readily penetrates into the CNS to give selective occupancy of GABA(A) alpha5 receptors. In addition, 43 enhances cognitive performance in rats in the delayed 'matching-to-place' Morris water maze test-a hippocampal-dependent memory task-without the convulsant or proconvulsant activity associated with nonselective, GABA(A) receptor inverse agonists.

引用

页码：2227 / 2240

页数：14

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