Open AccessElectrophysiological characterization of a novel Kv channel blocker N , N ′‐[oxy bis (2,1‐ethanediyloxy‐2,1‐ethanediyl)] bis (4‐methyl)‐benzenesulfonamide found in virtual screening 1
Author(s) -
GAO Zhaobing,
CHEN Xueqin,
JIANG Hualiang,
LIU Hong,
HU Guoyuan
Publication year - 2008
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2008.00777.x
Subject(s) - electrophysiology , chemistry , patch clamp , biophysics , intracellular , channel blocker , allosteric regulation , potassium channel , stereochemistry , biochemistry , receptor , biology , neuroscience , organic chemistry , calcium
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 ( I K ) and fast transient K + currents ( I A ) with IC 50 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 I K , without a significant effect on that of I A. OMBSA did not change the activation, steady‐state inactivation of I K , 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.