Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent.
Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent.
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发现4-芳基噻吩-3-羧酸作为ANO1的抑制剂及其作为镇痛剂的作用。
DOI：
10.1016/j.apsb.2020.11.004
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Wang Y;Gao J;Zhao S;Song Y;Huang H;Zhu G;Jiao P;Xu X;Zhang G;Wang K;Zhang L;Liu Z
anoctamin 1（ANO1）是一种参与神经去极化的钙激活氯离子通道。ANO1抑制剂通过局部外周给药和鞘内给药显示出显著的镇痛活性。在本研究中，通过基于形状的虚拟筛选，确定了几种噻吩羧酸和苯甲酸衍生物为新型ANO1抑制剂，其中设计并合成了具有最佳ANO1抑制活性的4 - 芳基噻吩 - 3 - 羧酸类似物，最终得到化合物42（半数抑制浓度（IC50） = 0.79 μmol/L）。化合物42选择性抑制ANO1，而不影响ANO2和细胞内钙离子浓度。随后，在疼痛模型中通过灌胃给药研究其镇痛效果。化合物42显著减轻了福尔马林和慢性压迫损伤诱导的痛觉过敏。通过同源建模和分子动力学模拟，预测其结合位点位于α6和α8之间的钙结合区域附近。我们的研究证实了ANO1抑制剂通过灌胃给药具有显著的镇痛效果，同时也为ANO1相关研究提供了选择性分子工具。
钙激活氯离子通道anoctamin 1（ANO1）是疼痛治疗的一个潜在靶点。发现了一系列新型4 - 芳基噻吩 - 3 - 羧酸化合物，它们能强烈且选择性地抑制ANO1通道，并通过口服减轻福尔马林和慢性压迫损伤诱导的痛觉过敏。
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. Calcium-activated chloride channel anoctamin 1 (ANO1) is a potential target for pain treatment. A novel series of 4-arylthiophene-3-carboxylic acid compounds are discovered to intensely and selectively suppress the ANO1 channel and orally attenuate allodynia which was induced by formalin and chronic constriction injury.
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