【摘 要】
：
Anoctamin 1(ANO1)is a kind of calcium-activated chloride channel involved in nerve de-polarization.ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration.In this study,several thiophenecarboxylic acid
【机 构】
：
State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking Univer
论文部分内容阅读
Anoctamin 1(ANO1)is a kind of calcium-activated chloride channel involved in nerve de-polarization.ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration.In this study,several thiophenecarboxylic acid and benzoic acid derivatives were identi-fied as novel ANO1 inhibitors through the shape-based virtual screening,among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed,synthe-sized and compound 42(IC50=0.79 μmol/L)was finally obtained.Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca2+concentration.Subsequently,the analgesic effect was investigated by intragastric administration in pain models.Compound 42 significantly attenuated al-lodynia which was induced by formalin and chronic constriction injury.Through homology modeling and molecular dynamics,the binding site was predicted to be located near the calcium-binding region be-tween α6 and α8.Our study validates ANO1 inhibitors having a significant analgesic effect by intragas-tric administration and also provides selective molecular tools for ANO1-related research.
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