Subtype-selective inhibition of acid-sensing ion channel 3 by a natural flavonoid.
Subtype-selective inhibition of acid-sensing ion channel 3 by a natural flavonoid.
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天然类黄酮对酸敏感离子通道 3 的亚型选择性抑制
DOI：
10.1111/cns.12979
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发表时间：
2019
影响因子：
5.5
通讯作者：
Liu jian-Hua
中科院分区：
文献类型：
--
作者：
Yan Xiao-Gang;Li Wei-Guang;Qi Xin;Zhu Jia-Jie;Huang Chen;Han Shao-Ling;Jiang Qin;Xu Tian-Le;Liu jian-Hua
目的酸敏感离子通道（ASICs）是细胞外质子门控阳离子通道，参与多种生理和病理过程，外周ASIC 3显著参与慢性疼痛、瘙痒和神经炎症的发病机制，这就需要以亚型特异性的方式发现和开发新的调节剂。结果我们鉴定了一种天然类黄酮化合物表没食子儿茶素没食子酸酯（EGCG，compound 11），它以亚型特异性的方式作为ASIC 3通道的有效抑制剂。在pH 5.0时，化合物11抑制ASIC 3电流，其表观半数抑制浓度为13.2 μmol/L。当浓度达到100 μmol/L时，化合物11对ASIC 1a、1b和2a通道无明显影响。与大多数已知的通常带有碱性或羧基的ASIC抑制剂相反，化合物11属于多酚家族。在化合物11中，除了没食子酸酯部分的完整性之外，其连苯三酚部分的手性和3-羟基基团对于抑制功效至关重要。最后，EGCG被发现显着降低小鼠酸诱导的疼痛反应behavior. ConclusionTogether，这些结果因此定义了一种新的骨架结构的小分子药物设计靶向ASIC 3通道治疗疼痛相关疾病。
AimsAcid‐sensing ion channels (ASICs) are extracellular proton‐gated cation channels that have been implicated in multiple physiological and pathological processes, and peripheral ASIC3 prominently participate into the pathogenesis of chronic pain, itch, and neuroinflammation, which necessitates the need for discovery and development of novel modulators in a subtype‐specific manner.MethodsWhole‐cell patch clamp recordings and behavioral assays were used to examine the effect of several natural compounds on the ASIC‐mediated currents and acid‐induced nocifensive behavior, respectively.ResultsWe identified a natural flavonoid compound, (‐)‐epigallocatechin gallate (EGCG, compound11), that acts as a potent inhibitor for the ASIC3 channel in an isoform‐specific way. The compound11inhibited ASIC3 currents with an apparent half maximal inhibitory concentration of 13.2 μmol/L when measured at pH 5.0. However, at the concentration up to 100 μmol/L, the compound11had no significant impacts on the homomeric ASIC1a, 1b, and 2a channels. In contrast to most of the known ASIC inhibitors that usually bear either basic or carboxylic groups, the compound11belongs to the polyphenolic family. In compound11, both the chirality and the 3‐hydroxyl group of its pyrogallol part, in addition to the integrity of the gallate part, are crucial for the inhibitory efficacy. Finally, EGCG was found significantly to decrease the acid‐induced nocifensive behavior in mice.ConclusionTaken together, these results thus defined a novel backbone structure for small molecule drug design targeting ASIC3 channels to treat pain‐related diseases.