ACCELERATED COMMUNICATION Identification of Novel and Selective KV2 Channel Inhibitors

Identification of selective ion channel inhibitors represents a critical step for understanding the physiological role that these proteins play in native systems. In particular, voltage-gated potassium (KV2) channels are widely expressed in tissues such as central nervous system, pancreas, and smooth muscle, but their particular contributions to cell function are not well understood. Although potent and selective peptide inhibitors of KV2 channels have been characterized, selective small molecule KV2 inhibitors have not been reported. For this purpose, highthroughput automated electrophysiology (IonWorks Quattro; Molecular Devices, Sunnyvale, CA) was used to screen a 200,000-compound mixture (10 compounds per sample) library for inhibitors of KV2.1 channels. After deconvolution of 190 active samples, two compounds (A1 and B1) were identified that potently inhibit KV2.1 and the other member of the KV2 family, KV2.2 (IC50, 0.1–0.2 ), and that possess good selectivity over KV1.2 (IC50 10 ). Modeling studies suggest that these compounds possess a similar three-dimensional conformation. Compounds A1 and B1 are 10-fold selective over NaV channels and other KV channels and display weak activity (5–9 ) on CaV channels. The biological activity of compound A1 on native KV2 channels was confirmed in electrophysiological recordings of rat insulinoma cells, which are known to express KV2 channels. Medicinal chemistry efforts revealed a defined structure-activity relationship and led to the identification of two compounds (RY785 and RY796) without significant CaV channel activity. Taken together, these newly identified channel inhibitors represent important tools for the study of KV2 channels in biological systems.