Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype.
Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype.
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DOI：
10.1016/j.bmcl.2022.128841
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发表时间：
2022-09-01
影响因子：
2.7
通讯作者：
Wipf, Peter
中科院分区：
文献类型：
--
作者：
Hernandez, Ciria C.;Tarfa, Rahilla A.;Limcaoco, Jose Miguel I.;Liu, Ruiting;Mondal, Pravat;Hill, Clare;Duncan, R. Keith;Tzounopoulos, Thanos;Stephenson, Corey R. J.;O'Meara, Matthew J.;Wipf, Peter
为了鉴定Kv7.2钾离子通道上的孔结构配体，我们在一系列试验中比较了野生型（WT）和W236L突变型Kv7.2通道与先前验证的和新的激动剂化学型。阳性对照为瑞加滨、氟吡汀和RL-81；即Kv7.2通道激活剂，在5 μM下显著地将电压依赖性激活转移到更负的电位（ΔV50）。我们发现了6种新的化合物，它们在WT和W236L突变体通道之间表现出不同的增强活性。全细胞膜片钳电生理研究鉴定Kv7.2。Kv7.2/3, Kv7.4和Kv7.5选择性。我们的结果验证了SyncroPatch平台，并建立了新的结构活性关系（SAR）。具体来说，除了选择性的Kv7.2, Kv7.2/3, Kv7.4。和Kv7.5激动剂，我们确定了一种新的化学型，ZK-21，一种不同于任何先前描述的Kv7通道调节剂的4-氨基四氢喹啉。通过柔性受体对接，ZK-21被W236稳定，并与雷吉滨垂直结合，将氨基甲酸苄酯基埋在一个到达孔域核心的隧道中。
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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影响因子：
2
作者：
Kazancioglu MZ;Quirion K;Wipf P;Skoda EM
通讯作者：
Skoda EM
影响因子：
44.1
作者：
Li, Xiaoxiao;Zhang, Qiansen;Guo, Jiangtao
通讯作者：
Guo, Jiangtao
DOI：
10.1073/pnas.1302770110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Li, Shuang;Choi, Veronica;Tzounopoulos, Thanos
通讯作者：
Tzounopoulos, Thanos
影响因子：
7.3
作者：
Zhang, Yang-Ming;Xu, Hai-Yan;Nan, Fa-Jun
通讯作者：
Nan, Fa-Jun
分子对接中的配体姿势和定向抽样。
影响因子：
3.7
作者：
Coleman RG;Carchia M;Sterling T;Irwin JJ;Shoichet BK
通讯作者：
Shoichet BK