Yu Haibo, Lin Zhihong, Xu Kaiping, Huang Xiaofang, Long Shunyou, Wu Meng, McManus Owen B., Le Engers Julie, Mattmann Margrith E., Engers Darren W., Le Uyen M., Lindsley Craig W., Hopkins Corey R., Li Min
Johns Hopkins Ion Channel Center
Vanderbilt Specialized Chemistry Center for Accelerated Probe Development
KCNQ voltage-gated potassium channels are involved in regulating excitability, action potential duration and transport processes in a variety of cell types. A high throughput fluorescent screen based depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the Molecular Libraries Probe Production Centers Network (MLPCN) library to identify activators of KCNQ1 channels. Identified hits were characterized using IonWorks automated electrophysiology. An initial racemic hit (EC = 1.7 μM) served as a starting point for optimization studies of newly synthesized compounds. ML277 was identified as a potent (EC = 0.26 μM) activator of KCNQ1 channels with more than 100-fold selectivity for activation of KCNQ1 channels compared with closely related KCNQ2 and KCNQ4 channels and with distantly related hERG potassium channels. ML277 provides a novel and selective chemical probe to investigate the role of KCNQ1 channels.
KCNQ电压门控钾通道参与调节多种细胞类型的兴奋性、动作电位持续时间和转运过程。我们开发了一种基于高通量荧光筛选的去极化触发铊通过KCNQ1通道内流的方法，并用于筛选分子文库探针生产中心网络（MLPCN）文库，以鉴定KCNQ1通道的激活剂。使用IonWorks自动电生理技术对鉴定出的活性化合物进行表征。最初的外消旋活性化合物（EC = 1.7 μM）作为新合成化合物优化研究的起点。ML277被鉴定为KCNQ1通道的强效激活剂（EC = 0.26 μM），与密切相关的KCNQ2和KCNQ4通道以及远亲的hERG钾通道相比，对KCNQ1通道激活的选择性超过100倍。ML277为研究KCNQ1通道的作用提供了一种新型的选择性化学探针。
