Identification of a novel, small molecule inhibitor of KCNQ2 channels

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 (IC₅₀ = 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.