作为认知增强剂的选择性口服活性γ-氨基丁酸Aα5受体反向激动剂。

Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers.

作者信息

Sternfeld Francine, Carling Robert W, Jelley Richard A, Ladduwahetty Tamara, Merchant Kevin J, Moore Kevin W, Reeve Austin J, Street Leslie J, O'Connor Desmond, Sohal Bindi, Atack John R, Cook Susan, Seabrook Guy, Wafford Keith, Tattersall F David, Collinson Neil, Dawson Gerard R, Castro José L, MacLeod Angus M

机构信息

The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK.

出版信息

J Med Chem. 2004 Apr 22;47(9):2176-9. doi: 10.1021/jm031076j.

DOI:10.1021/jm031076j

PMID:15084116

Abstract

Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.

摘要

作用于γ-氨基丁酸A（GABA-A）苯二氮䓬结合位点的非选择性反向激动剂在动物中有认知增强作用，但具有致焦虑性且可引发惊厥。在此，我们描述了新型GABA-A α5亚型反向激动剂，从而鉴定出16号化合物为一种口服活性、功能选择性化合物，其可增强动物认知，且无致焦虑或惊厥作用。这类化合物可能有助于对症治疗与阿尔茨海默病及相关痴呆症相关的记忆损害。