Abstract
Aim: N,N’-[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 (IK) and fast
transient K+ currents (IA) with IC50 values of 2.1±1.1 μmol/L and 27.8±1.5 μmol/L,
respectively. The inhibition was voltage independent. OMBSA markedly accelerated
the decay time course of IK, without a significant effect on that of IA. 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 IA and slowed down its
recovery from inactivation. Intracellular dialysis of OMBSA had no effect on both
IK and IA. Conclusion: The results demonstrate that OMBSA blocks both IK and
IA 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.