Antinociceptive effects of novel epibatidine analogs through activation of α4β2 nicotinic receptors  

作　　者：Weiwei Li Jingyi Cai Benjamin H Wang Lanting Huang Jing Fan Yun Wang 

机构地区：[1]Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative innovation Center for Brain Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China [2]Department of Anesthesiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003,China [3]east shanghai high school [4]shanghai high school international division

出　　处：《Science China(Life Sciences)》2018年第6期688-695,共8页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(31471027,81400895 to Yun Wang and Weiwei Li)

摘　　要：The study of α4β2 nicotinic receptors has provided new indications in the treatment of pain. Efforts have been made to explore new α4β2 nicotinic receptor agonists, including TC-2559, as antinociceptive drugs. In this study, we discovered a set of novel epibatidine analogs with strong binding affinities to the α4β2 nicotinic receptors. Among these compounds, C-159, C-163, and C-9515 attenuated formalin-induced nociceptive responses in mice; C-9515 caused the most potent analgesic effect, which was blocked by mecamylamine, a non-selective nicotinic receptor antagonist. Furthermore, C-9515 potently inhibited chronic constriction injury(CCI)-induced neuropathic pain in rats, which was sensitive to DHβE, a selective α4β2 subtype antagonist,indicating that its analgesic effect was mediated by the activation of the α4β2 nicotinic receptors. In conclusion, the epibatidine analog C-9515 was found to be a potent α4β2 nicotinic receptor agonist with potent analgesic function, which demonstrated potential for the further exploration of its druggability.The study of α4β2 nicotinic receptors has provided new indications in the treatment of pain. Efforts have been made to explore new α4β2 nicotinic receptor agonists, including TC-2559, as antinociceptive drugs. In this study, we discovered a set of novel epibatidine analogs with strong binding affinities to the α4β2 nicotinic receptors. Among these compounds, C-159, C-163, and C-9515 attenuated formalin-induced nociceptive responses in mice; C-9515 caused the most potent analgesic effect, which was blocked by mecamylamine, a non-selective nicotinic receptor antagonist. Furthermore, C-9515 potently inhibited chronic constriction injury（CCI）-induced neuropathic pain in rats, which was sensitive to DHβE, a selective α4β2 subtype antagonist,indicating that its analgesic effect was mediated by the activation of the α4β2 nicotinic receptors. In conclusion, the epibatidine analog C-9515 was found to be a potent α4β2 nicotinic receptor agonist with potent analgesic function, which demonstrated potential for the further exploration of its druggability.

关 键 词：α4β2 nicotinic receptor pain formalin test chronic constriction injury 

分 类 号：R402[医药卫生—临床医学]