2. Academic Validation
  3. Design, synthesis, and biological evaluation of new bis-benzylisoquinoline-based analogues as potential neuromuscular blocking agents

Design, synthesis, and biological evaluation of new bis-benzylisoquinoline-based analogues as potential neuromuscular blocking agents

  • Bioorg Med Chem Lett. 2024 May 10:108:129793. doi: 10.1016/j.bmcl.2024.129793.
Lin Fu 1,  Yu Gan 2,  Xiaofeng Liu 3,  Chen Chen 3,  Yi Zhao 2,  Yong Qin 1,  Gang Chen 3,  Hao Song 4,  Bowen Ke 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Central Nervous System Drug Key Laboratory of Sichuan Province, Sichuan Credit Pharmaceutical CO., Ltd., Luzhou, China.
  • 4 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. Electronic address: songhao@scu.edu.cn.
  • 5 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. Electronic address: bowenke@scu.edu.cn.
PMID: 38735343 DOI: 10.1016/j.bmcl.2024.129793
Abstract

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.

Keywords

Clinical Duration; Muscle Relaxation; Neuromuscular Blocking Agents; New Bis-Benzylisoquinoline-Based NMBA derivatives.

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