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Aim: N,No-[oxybis(2,1-ethanediyloxy-2,1-ethanediyl)]bis(4-methyl)- benzenesulfonamide (OMBSA) is a hit compound with potent voltage-gated K+ (Kv) channel-blocking activities that was found while searching the MDL Available Chemicals Directory with a virtual screening approach. In the present study, the blocking actions of OMBSA on Kv channels and relevant mechanisms were characterized., Methods: Whole-cell voltage-clamp recording was made in acutely dissociated hippocampal CA1 pyramidal neurons of newborn rats., Results: Superfusion of OMBSA reversibly inhibited both the delayed rectifier (I(K)) and fast transient K+ currents (I(A)) with IC50 values of 2.1+/-1.1 micromol/L and 27.8+/-1.5 micromol/L, respectively. The inhibition was voltage independent. OMBSA markedly accelerated the decay time course of IK, without a significant effect on that of I(A). OMBSA did not change the activation, steady-state inactivation of IK, and its recovery from inactivation, but the compound caused a significant hyperpolarizing shift of the voltage dependence of the steady-state inactivation of I(A) and slowed down its recovery from inactivation. Intracellular dialysis of OMBSA had no effect on both I(K) and I(A)., Conclusion: The results demonstrate that OMBSA blocks both I(K) and I(A) through binding to the outer mouth of the channel pore, as predicted by the molecular docking model used in the virtual screening. In addition, the compound differentially moderates the inactivation kinetics of the K+ channels through allosteric mechanisms.

Aim: To examine the effect of BmTx3B, a novel short-chain peptide isolated from the venom of Asian scorpion Buthus martensi Karsch, on voltage-gated potassium channels., Methods: Two types of voltage-dependent potassium currents were recorded from dissociated hippocampal neurons of neonatal rat in whole-cell voltage-clamp mode, and separated based upon their kinetic properties., Results: BmTx3B (10-100 micromol/L) selectively inhibited the delayed rectifier potassium current (I(K)), without affecting the fast transient potassium current (I(A)). The inhibition of the peptide on I(K) was reversible, concentration-dependent and voltage-independent. BmTx3B did not affect the steady-state activation and inactivation kinetics of the current., Conclusion: The short-chain scorpion peptide BmTx3B selectively blocked the delayed rectifier potassium channel.