J Pharmacol Exp Ther 2002 Jul 01;3021:314-9. doi: 10.1124/jpet.302.1.314.

Open channel block by KCB-328 [1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride] of the heterologously expressed human ether-a-go-go-related gene K+ channels.

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KCB-328 [1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride] is a newly synthesized class III antiarrhythmic drug and is known to be highly effective against various types of arrhythmias induced by coronary artery ligation, reperfusion, and programmed electrical stimulation. To understand the potential ionic mechanisms, we examined the effects of KCB-328, which encodes the rapidly activating delayed rectifier K(+) current in cardiac tissues, on human ether-a-go-go-related gene (HERG) channels expressed in Xenopus oocytes. The amplitudes of steady-state currents and tail currents of HERG were decreased by KCB-328 dose dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by KCB-328 is voltage-dependent. IC(50) values at -30, -20, -10, 0, +10, +20, +30, and +40 mV were 7.6 +/- 0.5, 4.8 +/- 0.4, 3.2 +/- 0.3, 2.1 +/- 0.3, 1.7 +/- 0.2, 1.4 +/- 0.2, 1.3 +/- 0.1, and 1.2 +/- 0.1 microM, respectively. Induction of block depended on depolarization beyond the threshold for channel opening. In addition, time-dependent block developed slowly, with tau = 1.7 +/- 0.3 s (100 microM) at 0 mV, and was delayed by a stronger depolarization to +80 mV, at which HERG channel is inactivated. We can conclude that KCB-328 preferentially blocks open (or activated) HERG channels. The block of HERG current might in part explain the underlying ionic mechanism for the antiarrhythmic and proarrhythmic effect of KCB-328.

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Species referenced: Xenopus
Genes referenced: gnao1 kcnh1 kcnh2 mapt