Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA.
J Pharmacol Exp Ther. 2010 Mar;332(3):1040-53. doi: 10.1124/jpet.109.161885. Epub 2009 Nov 25.
GABA(A) receptor (R) positive allosteric modulators that selectively modulate GABA(A)Rs containing beta(2)- and/or beta(3)- over beta(1)-subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"beta(2/3)-selective" GABA(A)R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show alpha-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABA(A)R positive allosteric modulators that demonstrate differential beta-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other beta(2/3)-subunit selective, alpha-subunit isoform-selective, BZ and nonBZ GABA(A) positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at beta(1)-subunit-containing GABA(A)Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA(A)R with BZ-like anxiolytic efficacy by reducing or eliminating activity at beta(1)-subunit-containing GABA(A)Rs.
在不同的化学类型中，已经报道了 GABA(A) 受体 (R) 阳性变构调节剂，这些调节剂选择性调节含有β(2)-和/或β(3)-亚基的 GABA(A)R，而不是β(1)-亚基。例如 loreclezole、mefenamic acid、tracazolate 和 etifoxine。一般来说，“β(2/3)-选择性”GABA(A)R 阳性变构调节剂是非苯二氮䓬类药物（nonBZs），不显示 α 亚基同工型选择性，但在动物模型和人类中具有抗焦虑作用，且减少共济失调/镇静作用。在这里，我们报告了一对非苯二氮䓬类 GABA(A)R 阳性变构调节剂的对映体，它们表现出不同的β-亚基同工型选择性。我们已经使用电生理学、药代动力学和行为学测定法，对该对映体以及一系列其他β(2/3)-亚基选择性、α-亚基同工型选择性、BZ 和非苯二氮䓬类 GABA(A)阳性变构调节剂进行了测试，以检验以下假设：共济失调可能与β(1)-亚基含有 GABA(A)R 的调制程度相关。我们的发现为设计具有苯二氮䓬类抗焦虑功效的 GABA(A)R 变构调节剂提供了一种替代策略，通过减少或消除β(1)-亚基含有 GABA(A)R 的活性，从而获得具有抗焦虑作用的选择性变构调节剂。
