Synthesis and biological evaluation of novel lidocaine derivatives
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 13CNMR,1HNMR and HRMS.The binding affinity of the compounds for human sodium channel 1.7(hNav1.7)and 1.5(hNav1.5)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 Freund's 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 hNav 1.7 and hNav 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.
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