A-272651

The large‐conductance Ca2+‐activated K+channel (BKCa, KCa1.1) links membrane excitability with intracellular Ca2+signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BKCachannel blocker, 2,4‐dimethoxy‐N‐naphthalen‐2‐yl‐benzamide (A‐272651).

86Rb+efflux in HEK‐293 cells expressing BKCawas measured. Effects of A‐272651 on BKCaα‐ and BKCaαβ1‐mediated currents were evaluated by patch‐clamp. Effects on contractility were assessed using low‐frequency electrical field stimulated pig detrusor and spontaneously contracting guinea pig detrusor. Effects of A‐272651 on neuronal activity were determined in rat small diameter dorsal root ganglia (DRG).

A‐272651 (10 μM) inhibited86Rb+efflux evoked by NS‐1608 in HEK‐293 cells expressing BKCacurrents. A‐272651 concentration‐dependently inhibited BKCacurrents with IC50values of 4.59 μM (Hill coefficient 1.04, measured at +40 mV), and 2.82 μM (Hill coefficient 0.89), respectively, for BKCaα and BKCaαβ1‐mediated currents. Like iberiotoxin, A‐272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC50values of 4.05±0.05 and 37.95±0.12 μM, respectively. In capsaicin‐sensitive DRG neurons, application of A‐272651 increased action potential firing and prolonged action potential duration.

These data demonstrate that A‐272651 modulates smooth muscle contractility and neuronal firing properties. Unlike previously reported peptide BKCablockers, A‐272651 represents one of the first small molecule BKCachannel blockers that could serve as a useful tool for further characterization of BKCachannels in physiological and pathological states.British Journal of Pharmacology(2007)151, 798–806; doi:10.1038/sj.bjp.0707278