Developing dual functional allosteric modulators of GABAA receptors

被引：13

作者：

Liu, Xiaodong F. ^{[1
]}

Chang, Hui-Fang ^{[2
]}

Schmiesing, Richard Jon ^{[2
]}

Wesolowski, Steven S. ^{[2
]}

Knappenberger, Katharine S. ^{[1
]}

Arriza, Jeffrey L. ^{[1
]}

Chapdelaine, Marc J. ^{[2
]}

机构：

[1] AstraZeneca, Dept Neurosci Biol, Wilmington, DE 19850 USA

[2] AstraZeneca, Dept Chem, Wilmington, DE 19850 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 23期

关键词：

GABAA receptor; Benzodiazepine; Allosteric modulator; Subtype selectivity; Inverse agonist; Cinnoline; Quinoline; Anxiety; Cognition; TEVC; ALZHEIMERS-DISEASE; ANXIETY; BENZODIAZEPINES; COGNITION; SUBTYPE; SCHIZOPHRENIA; DENSITY; TPA023;

D O I：

10.1016/j.bmc.2010.09.058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Positive modulators at benzodiazepine sites of alpha 2- and alpha 3-containing GABA(A) receptors are believed to be anxiolytic. Negative allosteric modulators of alpha 5-containing GABA(A) receptors enhance cognition. By oocyte two-electrode voltage clamp and subsequent structure-activity relationship studies, we discovered cinnoline and quinoline derivatives that were both positive modulators at alpha 2-/alpha 3-containing GABA(A) receptors and negative modulators at alpha 5-containing GABA(A) receptors. In addition, these compounds showed no functional activity at alpha 1-containing GABA(A) receptors. Such dual functional modulators of GABA(A) receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：8374 / 8382

页数：9

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