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Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2020-11-17 , DOI: 10.1016/j.apsb.2020.11.004
Yuxi Wang 1 , Jian Gao 1 , Song Zhao 2 , Yan Song 1 , Han Huang 1 , Guiwang Zhu 1 , Peili Jiao 1 , Xiangqing Xu 2 , Guisen Zhang 3 , Kewei Wang 4 , Liangren Zhang 1 , Zhenming Liu 1
Affiliation  

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified 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, synthesized 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 allodynia 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 between α6 and α8. Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research.



中文翻译:

4-芳基噻吩-3-羧酸作为ANO1抑制剂的发现及其作为镇痛剂的作用

Anoctamin 1 (ANO1) 是一种钙激活的氯离子通道,参与神经去极化。ANO1 抑制剂通过局部外周和鞘内给药显示出显着的镇痛活性。本研究通过基于形状的虚拟筛选将几种噻吩羧酸和苯甲酸衍生物鉴定为新型 ANO1 抑制剂,其中设计合成了具有最佳 ANO1 抑制活性的 4-芳基噻吩-3-羧酸类似物并合成了化合物42 (IC 50  = 0.79 μmol/L) 最终得到。化合物42选择性抑制ANO1而不影响ANO2和细胞内Ca 2+专注。随后,通过在疼痛模型中胃内给药研究镇痛作用。化合物42显着减轻由福尔马林和慢性收缩损伤引起的异常性疼痛。通过同源建模和分子动力学,预测结合位点位于α 6 和α 8之间的钙结合区附近。我们的研究证实了 ANO1 抑制剂通过胃内给药具有显着的镇痛作用,并为 ANO1-提供了选择性的分子工具。相关的研究。

更新日期:2020-11-17
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