The identification of potent nonopioid analgesics and their potential for perioperative use
Abstract
Development of potent nonopioid analgesics (NOAs) has attracted great attentions from both academic and industrial worlds, aiming at replacing current opioid drugs in acute and chronic pain management. Among the diverse proposed pathways toward nonopioid analgesia, voltage-gated sodium channel stood out as one of the most promising targets in developing potent NOA. Diverging from the prevailing focus on highly subtype-selective blockers, we report here the access of potent analgesia via the simultaneous inhibition on multianalgesic-related sodium channel subtypes. Originated from AI-driven drug discovery and computer-aided drug design, the hit and lead compounds exhibited efficient inhibitory effect on analgesic-related sodium channel subtypes, robust analgesic effect in various rat models and no opioid-related adverse reactions. Furthermore, the potential of such a multi-subtype sodium channel blocker for perioperative use was validated through a surgical simulation. These findings represent a meaningful leap toward the goal of replacing opioids in perioperative period and provide fresh insights for future NOA development.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Chaoyi Deng
Department of Anesthesiology, West China Hospital, Sichuan University
Yu Deng
Xudong Luo
Department of Pharmacy, West China Hospital, Sichuan University
Junyu Lu
Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University
Chenyang Li
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics
Peiwen Gao
Department of Anesthesiology, West China Hospital, Sichuan University
Xiaoyu Xie
Department of Anesthesiology, West China Hospital, Sichuan University
Bingbing Xiang
International Center of Future Science, Jilin University, 2699 Qianjin Street, Changchun 130012, P. R. China
Sicheng Liu
Department of Chemistry
Xingxing Liu
State Key Laboratory of Loess Science, Institute of Earth Environment, Chinese Academy of Sciences
Xiaoxiao Li
Department of Anesthesiology, West China Hospital, Sichuan University
Pan Chang
Department of Anesthesiology, West China Hospital, Sichuan University
Xia Wu
Tufts Medicine Myeloma and Amyloid Program Tufts Medical Center Boston Massachusetts USA
Guoyan Zhao
Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University
Deying Gong
Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University
Jing Wang
Hunan Cancer Hospital Changsha China
Cheng Zhou
Department of Anesthesiology, West China Hospital, Sichuan University
Jin Liu
Tao Zhu
Zhejiang Key Laboratory of Precise Synthesis of Functional Molecules, Department of Chemistry, School of Science and Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Hangzhou 310030, Zhejiang Province, P. R. China
Fengming Luo
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University
Wensheng Zhang