α-氨基酸酚酯衍生物：新型水溶性全身麻醉剂，可别构调节γ-氨基丁酸A型（GABA(A)）受体。

Alpha-amino acid phenolic ester derivatives: novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors.

作者信息

Anderson A, Belelli D, Bennett D J, Buchanan K I, Casula A, Cooke A, Feilden H, Gemmell D K, Hamilton N M, Hutchinson E J, Lambert J J, Maidment M S, McGuire R, McPhail P, Miller S, Muntoni A, Peters J A, Sansbury F H, Stevenson D, Sundaram H

机构信息

Organon Research, Newhouse, Lanarkshire ML1 5SH, Scotland, U.K.

出版信息

J Med Chem. 2001 Oct 25;44(22):3582-91. doi: 10.1021/jm010903i.

DOI:10.1021/jm010903i

PMID:11606122

Abstract

In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg.

摘要

在寻找新型水溶性全身麻醉剂的过程中，从专利文献中鉴定出的一种α-氨基酸酚酯先导化合物的活性得到了显著提高。除了提高在小鼠体内的活性外，它在体外对GABA(A)受体也具有良好的活性。在该系列化合物中，发现其在体外和体内活性均具有良好的对映选择性，这支持了一种涉及GABA(A)受体变构调节的蛋白质介导的麻醉作用机制。α-氨基酸酚酯19，作为氢溴酸盐Org 25435，因其保留了最佳的整体麻醉特性以及改善的稳定性和水溶性而被选用于临床评估。在临床上，它被证明是一种有效的人体静脉麻醉剂，在3和4mg/kg的剂量下麻醉起效快且恢复快。