Yu Haibo, Xu Kaiping, Zou Beiyan, Wu Meng, McManus Owen B., Le Engers Julie, Cheung Yiu-Yin, Salovich James M., Hopkins Corey R., Lindsley Craig W., Li Min
Johns Hopkins Ion Channel Center
Vanderbilt Specialized Chemistry Center for Accelerated Probe Development
A high-throughput screen (HTS) of the Molecular Libraries Probe Centers Network (MLPCN) library was performed using a thallium influx assay in order to identify inhibitors of potassium voltage-gated channel, KQT-like subfamily, member 2 (KCNQ2) channels. Structure activity relationship (SAR) studies of active compounds yielded ML252, a potent (IC = 69 nM) inhibitor of KCNQ2 channels in electrophysiological assays. ML252 displayed more than forty-fold selectivity for blocking KCNQ2 channels compared with KCNQ1 channels. SAR studies revealed a site on ML252 at which small structural changes caused a functional shift from antagonist to agonist activity, suggesting that ML252 interacted with a critical site for controlling gating of KCNQ2 channels. ML252 represents a novel and potent inhibitor of KCNQ2 channels with a selectivity profile that enables use of the probe for investigating the role of KCNQ2 channels in neuronal function.
利用铊流入测定法对分子文库探针中心网络（MLPCN）文库进行了高通量筛选（HTS），以鉴定钾电压门控通道KQT样亚家族成员2（KCNQ2）通道的抑制剂。对活性化合物的构效关系（SAR）研究产生了ML252，它在电生理测定中是一种有效的（IC = 69 nM）KCNQ2通道抑制剂。与KCNQ1通道相比，ML252对阻断KCNQ2通道表现出超过40倍的选择性。SAR研究揭示了ML252上的一个位点，在该位点上微小的结构变化会导致功能从拮抗剂活性转变为激动剂活性，这表明ML252与控制KCNQ2通道门控的关键位点相互作用。ML252代表了一种新型的、有效的KCNQ2通道抑制剂，其选择性特征使其能够作为探针用于研究KCNQ2通道在神经元功能中的作用。
