A newly developed anesthetic based on a unique chemical core
A newly developed anesthetic based on a unique chemical core
复制标题
DOI：
10.1073/pnas.1822076116
复制
发表时间：
2019-07-30
影响因子：
11.1
通讯作者：
Bertaccini, Edward J.
中科院分区：
文献类型：
--
作者：
Cayla, Noelie S.;Dagne, Beza A.;Bertaccini, Edward J.
静脉麻醉剂与心血管不稳定有关，并且在患有心血管疾病、创伤或急性全身性疾病的患者中耐受性差。我们假设，一种新型的静脉（IV）麻醉剂分子，对缓慢类型的麻醉具有高度选择性。氨基丁酸A型受体（GABA（A）R）具有强效麻醉作用，但心血管效应有限。通过使用我们的GABA（A）R模型的计算机筛选，我们鉴定了一类先导化合物，它们是N-芳基吡咯衍生物。使用体外表达系统和完整的啮齿动物海马脑切片记录的电生理学分析证明了GABA（A）R介导的机制。体内实验也证明了在蝌蚪和大鼠中的明显麻醉活性，其效力略高于丙泊酚。与临床批准的GABA能麻醉剂依托咪酯不同，我们的N-芳基吡咯衍生物的化学结构不含产生肾上腺抑制的化学部分。我们这类化合物对血压的抑制作用也很小，甚至没有，这与丙泊酚的血流动力学作用形成鲜明对比。这些化合物来源于以前与麻醉无关的化学结构，并证明选择性靶向GABA（A）R-慢亚型可以消除与常规IV麻醉剂相关的血液动力学副作用。
Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that is highly selective for the slow type of.-aminobutyric acid type A receptor (GABA(A)R) could have potent anesthetic efficacy with limited cardiovascular effects. Through in silico screening using our GABA(A)R model, we identified a class of lead compounds that are N-arylpyrrole derivatives. Electrophysiological analyses using both an in vitro expression system and intact rodent hippocampal brain slice recordings demonstrate a GABA(A)R-mediated mechanism. In vivo experiments also demonstrate overt anesthetic activity in both tadpoles and rats with a potency slightly greater than that of propofol. Unlike the clinically approved GABAergic anesthetic etomidate, the chemical structure of our N-arylpyrrole derivative is devoid of the chemical moieties producing adrenal suppression. Our class of compounds also shows minimal to no suppression of blood pressure, in marked contrast to the hemodynamic effects of propofol. These compounds are derived from chemical structures not previously associated with anesthesia and demonstrate that selective targeting of GABA(A)R-slow subtypes may eliminate the hemodynamic side effects associated with conventional IV anesthetics.