Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan Province, China.
Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China.
Bioorg Med Chem Lett. 2024 Aug 1;108:129793. doi: 10.1016/j.bmcl.2024.129793. Epub 2024 May 10.
Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA.
神经肌肉阻断剂（NMBAs）广泛用于麻醉中的插管和外科肌肉松弛。新型阿曲库铵和米库氯铵衍生物被开发出来，化合物 18c、18d 和 29a 在 27.27 nmol/kg 时表现出类似于米库氯铵的松弛作用，而化合物 15b、15c、15e 和 15h 在 272.7 nmol/kg 时具有更短的作用持续时间。通过分子对接分析了这些衍生物以及 29a 与烟碱型乙酰胆碱受体结合的结构-活性和构象-活性关系。兔试验表明，与米库氯铵相比，化合物 29a 的作用持续时间更短。这表明连接基团性质、铵基团取代基和构型对于 NMBA 的活性和作用持续时间至关重要，化合物 29a 可能成为一种潜在的超短效 NMBA。
