Synthesis And Analgesic Activity Of The Lappaconitine Derivatives

As the first non-addictive analgesic drug in China,lappaconitine has remarkable analgesic activity.However,its wide application is limited by its high toxicity and poor water solubility.Accordingly,the investigation of synthetic transformations of lappaconitine in order to discover new derivatives that combine higher biological activity and lower toxicity is of considerable importance.A series of lappaconitine derivatives（1-25）for analgesic activity in vivo via hot-plate test and acetic acid-induced writhing assay in mice were designed and synthesized in this study.The results showed that all compounds exhibited analgesic activity except compound15,which was too toxic to be tested.In particular,analgesic activity of compounds 16(ED₅₀=1.89 mg/kg)and 20(ED₅₀=2.56 mg/kg)were superior to lappaconitine(ED₅₀=3.50mg/kg),and compounds 9,10,24 showed good analgesic activity(ED₅₀=7.25,8.33,and5.96 mg/kg,respectively).Acute toxicity results showed compounds 16(LD₅₀=9.28 mg/kg)and 20(LD₅₀=7.69 mg/kg)had a similar toxicity to lappaconitine(LD₅₀=11.70 mg/kg),and the toxicity of compound 24(LD₅₀=23.91 mg/kg)was lower than lappaconitine.Notably,the acute toxicity of compounds 9(LD₅₀>1000 mg/kg)and 10(LD₅₀>800 mg/kg)were significantly lower than lappaconitine while their analgesic activity retained as lappaconitine,which can be further studied as lead compounds.The structure–activity relationship data acquired for lappaconitine derivatives showed that the substituent of2′-amide of 4-O-2′-acetamidobenzoate side chain could affect the analgesic activity,especially the toxicity（compound 9 and 10）.The present findings not only enriched the diversity of bioactive diterpenoid alkaloids,but revealed the important structure-analgesic-toxicity relationships of lappaconitine analogues.Furthermore,the study provided analgesic lead compounds and candidate drugs with high biological activity and extremely low toxicity for further preclinical studies.