title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Chonbuk National University Medical School, Chonju 561-180, South Korea.
authors.forename: Jin-Bong
authors.initials: JB
authors.lastname: Park
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Yu-Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Ki-Chan
authors.initials: KC
authors.lastname: Ha
authors.forename: Kyoung-Suk
authors.initials: KS
authors.lastname: Rhee
authors.forename: Jae-Ki
authors.initials: JK
authors.lastname: Ko
authors.forename: Chan-Uhng
authors.initials: CU
authors.lastname: Joo
authors.forename: Soo-Wan
authors.initials: SW
authors.lastname: Chae
authors.forename: Yong-Geun
authors.initials: YG
authors.lastname: Kwak
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014981:Xenopus
chemical_list: C112304:1-(2-amino-4-methanesulfonamidophenoxy)-2-(N-(3,4-dimethoxyphenethyl)-N-methylamino)ethane; D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG