Liu Dian, Wang Jixia, Hou Tao, Zhang Yan, Zhou Han, Zhao Yaopeng, Zhou Liangliang, Cao Cuiyan, Liu Yanfang, Liang Xinmiao
Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Jiangxi Provincial Key Laboratory for Pharmacodynamic Material Basis of Traditional Chinese Medicine, Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China.
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
J Adv Res. 2025 Aug;74:637-649. doi: 10.1016/j.jare.2024.10.011. Epub 2024 Oct 24.
Opioids are the most common antinociceptive drugs, but long-term administration causes serious adverse side effects. Gelsemium elegans Benth. is traditionally used as an analgesic agent and mainly contains indole alkaloids with structures different from those in common opioids, indicating distinct pharmacological properties. This work aims to find a new analgesic from Gelsemium elegans Benth. and evaluate it in vitro and in vivo.
Dihydrokoumine was purified from Gelsemium elegans Benth. Binding to mu opioid receptor (MOR), M3 receptor (M3R) and other 15 G protein-coupled receptors were evaluated in vitro combined with molecular docking analysis. Analgesic efficacy and side effects were measured in vivo using hot-plate, formalin paw, and rotarod tests in mice. Cytotoxicity, acute toxicity in mice and pharmacokinetics were assessed.
A MOR agonist, dihydrokoumine, was first identified from Gelsemium elegans Benth. Further investigations showed that dihydrokoumine exhibited selective partial agonist action on the MOR and antagonist action on the M3R among other 15 GPCRs. In in vivo mouse models, dihydrokoumine could relieve acute pain and chronic inflammatory pain without drug tolerance and sedative side effects. Additionally, we observed a good safety profile and favorable pharmacokinetic properties.
A MOR partial agonist/M3R antagonist analgesic with reduced side effects was isolated from a traditional Chinese medicine. This study bestows dihydrokoumine as a new dual-target analgesic and as a potential lead compound in long-term pain management.
阿片类药物是最常用的抗伤害感受药物，但长期使用会导致严重的不良副作用。钩吻传统上用作镇痛剂，主要含有结构与常见阿片类药物不同的吲哚生物碱，表明其具有独特的药理特性。本研究旨在从钩吻中寻找一种新的镇痛药，并进行体外和体内评价。
从钩吻中纯化出二氢钩吻素甲。结合分子对接分析，体外评价其与μ阿片受体（MOR）、M3受体（M3R）及其他15种G蛋白偶联受体的结合情况。采用热板法、福尔马林致痛足跖法和小鼠转棒试验，在体内测定其镇痛效果和副作用。评估其细胞毒性、小鼠急性毒性和药代动力学。
首次从钩吻中鉴定出一种MOR激动剂——二氢钩吻素甲。进一步研究表明，二氢钩吻素甲对MOR表现出选择性部分激动作用，对M3R及其他15种G蛋白偶联受体表现出拮抗作用。在体内小鼠模型中，二氢钩吻素甲可缓解急性疼痛和慢性炎性疼痛，且无药物耐受性和镇静副作用。此外，我们观察到其具有良好的安全性和有利的药代动力学特性。
从一种中药中分离出一种副作用较小的MOR部分激动剂/M3R拮抗剂镇痛药。本研究赋予二氢钩吻素甲作为一种新型双靶点镇痛药以及长期疼痛管理中潜在先导化合物的地位。
