化学
兴奋剂
钾通道
化学型
突变体
离子通道
膜片钳
电生理学
立体化学
生物物理学
受体
药理学
生物化学
神经科学
生物
基因
色谱法
精油
作者
Ciria C. Hernández,Rahilla A. Tarfa,Jose Miguel I. Limcaoco,Ruiting Liu,Pravat Mondal,Clare Hill,R. Keith Duncan,Thanos Tzounopoulos,Corey R. J. Stephenson,Matthew J. O’Meara,Peter Wipf
标识
DOI:10.1016/j.bmcl.2022.128841
摘要
To identify pore domain ligands on Kv7.2 potassium ion channels, we compared wild-type (WT) and W236L mutant Kv7.2 channels in a series of assays with previously validated and novel agonist chemotypes. Positive controls were retigabine, flupirtine, and RL-81; i.e. Kv7.2 channel activators that significantly shift voltage-dependent activation to more negative potentials (ΔV50) at 5 µM. We identified 6 new compounds that exhibited differential enhancing activity between WT and W236L mutant channels. Whole cell patch-clamp electrophysiology studies were conducted to identify Kv7.2. Kv7.2/3, Kv7.4, and Kv7.5 selectivity. Our results validate the SyncroPatch platform and establish new structure activity relationships (SAR). Specifically, in addition to selective Kv7.2, Kv7.2/3, Kv7.4. and Kv7.5 agonists, we identified a novel chemotype, ZK-21, a 4-aminotetrahydroquinoline that is distinct from any of the previously described Kv7 channel modifiers. Using flexible receptor docking, ZK-21 was predicted to be stabilized by W236 and bind perpendicular to retigabine, burying the benzyl carbamate group into a tunnel reaching the core of the pore domain.
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