Development and SAR of functionally selective allosteric modulators of GABAA receptors

被引：48

作者：

Alhambra, Cristobal ^{[1
]}

Becker, Chris ^{[1
]}

Blake, Timothy ^{[1
]}

Chang, Amy ^{[1
]}

Damewood, James R., Jr. ^{[1
]}

Daniels, Thalia ^{[1
]}

Dembofsky, Bruce T. ^{[1
]}

Gurley, David A. ^{[3
]}

Hall, James E. ^{[1
]}

Herzog, Keith J. ^{[1
]}

Horchler, Carey L. ^{[1
]}

Ohnmacht, Cyrus J. ^{[1
]}

Schmiesing, Richard Jon ^{[1
]}

Dudley, Adam ^{[3
]}

Ribadeneira, Maria D. ^{[2
]}

Knappenberger, Katherine S. ^{[3
]}

Maciag, Carla ^{[3
]}

Stein, Mark M. ^{[3
]}

Chopra, Maninder ^{[3
]}

Liu, Xiaodong F. ^{[3
]}

Christian, Edward P. ^{[3
]}

Arriza, Jeffrey L. ^{[2
]}

Chapdelaine, Marc J. ^{[1
]}

机构：

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

[2] AstraZeneca, Dept Disposit Metab & Pharmacokinet, Wilmington, DE 19850 USA

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 09期

关键词：

GABA(A) receptor; Benzodiazepine; Allosteric modulator; Subtype functional selectivity; Cinnoline; Quinoline; Anxiety; DRUG DESIGN; BINDING; SITE;

D O I：

10.1016/j.bmc.2011.03.035

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 the benzodiazepine site of alpha 2- and alpha 3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at alpha 2-/alpha 3-containing GABA(A) receptors and that show no functional activity at alpha 1-containing GABAA receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the alpha 2- and alpha 3-containing GABA(A) receptors, while simultaneously neutral antagonists at alpha 1-containing GABAA receptors, is described. Such functionally selective modulators of GABA(A) receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：2927 / 2938

页数：12