Popik Piotr, Kostakis Emmanuel, Krawczyk Martyna, Nowak Gabriel, Szewczyk Bernadeta, Krieter Philip, Chen Zhengming, Russek Shelley J, Gibbs Terrell T, Farb David H, Skolnick Phil, Lippa Arnold S, Basile Anthony S
Behavioral Neuroscience, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
J Pharmacol Exp Ther. 2006 Dec;319(3):1244-52. doi: 10.1124/jpet.106.107201. Epub 2006 Sep 13.
Studies using mice with point mutations of GABA(A) receptor alpha subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA(A) receptors bearing the alpha(1) and alpha(2) subunits. This hypothesis predicts that a compound with high efficacy at GABA(A) receptors containing the alpha(1) subunit would produce sedation, whereas an agonist acting at alpha(2) subunit-containing receptors (with low or null efficacy at alpha(1)-containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA(A) receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at alpha(1)beta(2)gamma(2S) constructs of the GABA(A) receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing alpha(2), alpha(3), or alpha(5) subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test, an effect blocked by flumazenil, and increased the percentage of time spent in the open arms of the elevated plus-maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than 1 order of magnitude greater than the minimal effective anxiolytic dose. Although the mutant mouse data predict that the high-efficacy potentiation of GABA(A1a) receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by alpha(1) subunit-containing GABA(A) receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.
使用γ-氨基丁酸A（GABA(A)）受体α亚基点突变小鼠的研究表明，1,4-苯二氮䓬类药物的镇静和抗焦虑特性分别由含有α(1)和α(2)亚基的GABA(A)受体介导。该假说预测，对含有α(1)亚基的GABA(A)受体具有高效能的化合物会产生镇静作用，而作用于含有α(2)亚基的受体（对含有α(1)亚基的受体效能低或无效能）的激动剂将具有抗焦虑选择性。使用非洲爪蟾卵母细胞中表达的重组GABA(A)受体进行的电生理研究表明，吡唑并-[1,5-a]-嘧啶DOV 51892对GABA(A)受体α(1)β(2)γ(2S)构建体上GABA刺激电流的最大增强作用（148%）显著高于地西泮。相比之下，在增强由含有α(2)、α(3)或α(5)亚基的构建体介导的GABA刺激电流方面，DOV 51892的效能和/或效力远低于地西泮。在体内，DOV 51892增加了Vogel冲突试验中受罚反应，该效应可被氟马西尼阻断，并增加了高架十字迷宫开放臂中停留时间的百分比。然而，在比最小有效抗焦虑剂量大1个以上数量级的剂量下，DOV
51892对运动功能或肌肉松弛没有一致影响。尽管突变小鼠数据预测DOV 51892对GABA(A1a)受体介导电流的高效能增强作用会产生镇静作用，但行为学研究表明DOV 51892具有抗焦虑选择性，这表明由含有α(1)亚基的GABA(A)受体介导的GABA增强作用可能既不是苯二氮䓬识别位点调节剂镇静特性的唯一机制，也不是高度预测指标。
