Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
Eur J Pharmacol. 2012 Nov 5;694(1-3):13-9. doi: 10.1016/j.ejphar.2012.07.040. Epub 2012 Aug 23.
AZD3043 (previously named THRX-918661) is a novel short-acting intravenous anesthetic agent in clinical trials. Although AZD3043 is a positive modulator at the γ-aminobutyric acid (GABA)(A)-receptor, its potency and efficacy have not been characterized in detail. Nor is it known whether the point-mutations in the β-subunit of the GABA(A)-receptor that dramatically reduce the anesthetic effect of propofol (i.e. β2 (N289M) and β3 (N290M)), also influence the effect of AZD3043. This study investigated the in vitro pharmacology of AZD3043 at the most common human GABA(A) receptor subtypes. Subunits of four human wild-type (α1β2, α1β2γ2, α2β2γ2 and α2β3γ2) and two mutant (α1β2(N289M)γ2 and α2β3(N290M)γ2) GABA(A) receptor channels were introduced into Xenopus oocytes and studied with two-electrode voltage-clamp. AZD3043 potentiated and directly activated the α1β2γ2, α2β2γ2 and α2β3γ2 GABA(A) receptor subtypes. Moreover, both potency and efficacy of AZD3043 were reduced at the mutant α1β2(N289M)γ2 and α2β3(N290M)γ2 subtypes. AZD3043 increased the GABA response also in GABA(A) receptors lacking the γ2-subunit, i.e. α1β2. In conclusion, AZD3043 is a positive modulator and a direct agonist at human GABA(A) receptors and is not dependent on the γ2-subunit for its effect. Similar to propofol, the effect of AZD3043 is dramatically reduced by point-mutations in the β2(N289M) and β3(N290M) subunits, indicating similar molecular mechanisms of action for propofol and AZD3043 at the human GABA(A) receptor.
AZD3043（曾名为 THRX-918661）是一种新型的临床研究用短时效静脉麻醉剂。虽然 AZD3043 是 GABA（A）受体的正变构调节剂，但它的效力和功效尚未详细描述。也不知道 GABA（A）受体β亚单位的点突变（即β2（N289M）和β3（N290M））是否会显著降低异丙酚的麻醉效果，也会影响 AZD3043 的效果。本研究调查了 AZD3043 在最常见的人 GABA（A）受体亚型中的体外药理学。将四个野生型（α1β2、α1β2γ2、α2β2γ2 和 α2β3γ2）和两个突变型（α1β2（N289M）γ2 和 α2β3（N290M）γ2）的人 GABA（A）受体亚单位引入非洲爪蟾卵母细胞，并通过双电极电压钳进行研究。AZD3043 增强并直接激活了 α1β2γ2、α2β2γ2 和 α2β3γ2 GABA（A）受体亚型。此外，突变型 α1β2（N289M）γ2 和 α2β3（N290M）γ2 亚型的 AZD3043 的效力和功效均降低。AZD3043 还增加了缺乏 γ2 亚单位的 GABA（A）受体，即 α1β2 的 GABA 反应。总之，AZD3043 是人类 GABA（A）受体的正变构调节剂和直接激动剂，其作用不依赖于 γ2 亚单位。与异丙酚相似，β2（N289M）和 β3（N290M）亚单位的点突变显著降低了 AZD3043 的作用，表明异丙酚和 AZD3043 在人类 GABA（A）受体上具有相似的作用机制。
