新型利多卡因衍生物的合成与生物评价  

Synthesis and biological evaluation of novel lidocaine derivatives

作　　者：陈宇豪 陈春霞 康婷 柯博文[2] 齐庆蓉[1] CHEN Yuhao;CHEN Chunxia;KANG Ting;KE Bowen;QI Qingrong(West China School of Pharmacy,Sichuan University,Chengdu,Sichuan,610041 P.R.China;West China Hospital,Sichuan University,Chengdu,Sichuan,610041 P.R.China)

机构地区：[1]四川大学华西药学院,四川成都610041 [2]四川大学华西医院,四川成都610041

出　　处：《华西药学杂志》2024年第2期123-127,共5页West China Journal of Pharmaceutical Sciences

基　　金：国家自然科学基金资助项目(批准号:82273784)。

摘　　要：目的制备具有镇痛活性的新型利多卡因衍生物。方法基于利多卡因的构效关系进行结构修饰,用HPLC法测定化合物的纯度,通过碳谱、氢谱及高分辨质谱确证化合物的结构;通过细胞膜色谱技术测定化合物与人钠离子通道(hNav)1.7和hNav1.5的结合亲和力,优选出化合物,评价其在0.6%冰乙酸诱导的小鼠急性内脏痛扭体模型和完全氟氏佐剂诱导的小鼠慢性炎性痛模型中的镇痛效果,筛选出最优化合物,并评价其安全性。结果通过侧链改构获得5个利多卡因衍生物并确证其结构,测定5个化合物的纯度及其与hNav1.7和hNav1.5的结合亲和力,优选出化合物后并评价其在小鼠模型上的镇痛效果,选定最优化合物后评价其安全性。结论最优化合物LD2有良好的镇痛活性及较高的安全性,无心脏、肝脏、肾脏毒性,有作为镇痛药物开发的潜力。OBJECTIVE To synthesize the novel lidocaine derivatives with analgesic activity.METHODS The structural modification of lidocaine was based on its structure-activity relationship,and the purity of these compounds was determined by HPLC,and the structures of these compounds were confirmed by"3CNMR,'HNMR and HRMS.The binding affinity of the compounds for human sodium channel 1.7(hNa,1.7)and 1.5(hNa,1.5)were determined through cell membrane chromatography to further screen out the preferred compound.The analgesic effect of these compound was evaluated in mouse models of 0.6%acetic acid induced endogenous infliction pain(writhing test)and Complete Freunds Adjuvant(CFA)induced chronic inflammatory pain(paw withdrawl mechanical threshold),resulting the discovery of the optimal compound and evaluation of its safety profiles.RESULTS Five lidocaine derivatives were synthesized by side-chain modification and their structures were validated.The purity of these five compounds and their binding affinities to hNa,1.7 and hNa,1.5 were determined,and the analgesic efficacy of the preferred compounds was evaluated in mice models,and the safety profile was evaluated after selecting the optimal compound.CONCLUSION The optimal compound,LD2,exhibits good analgesic activity,sufficient safety and no significant toxicity to the liver,kidney and heart.Therefore LD2 has potential for further development as an analgesic drug.

关 键 词：利多卡因衍生物 新型镇痛药物 细胞膜色谱 构效关系 合成 药效学研究 安全性评价 

分 类 号：R914[医药卫生—药物化学]