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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.
J Pharmacol Exp Ther. 2002 Jul; 302(1):314-9.JP

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.

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Authors+Show Affiliations

Park JB
Department of Pharmacology, Chonbuk National University Medical School, Chonju 561-180, South Korea.
Choe H
No affiliation info available
Lee YK
No affiliation info available
Ha KC
No affiliation info available
Rhee KS
No affiliation info available
Ko JK
No affiliation info available
Joo CU
No affiliation info available
Chae SW
No affiliation info available
Kwak YG
No affiliation info available

MeSH

Action PotentialsAlgorithmsAnimalsAnti-Arrhythmia AgentsCation Transport ProteinsDNA-Binding ProteinsERG1 Potassium ChannelEther-A-Go-Go Potassium ChannelsHeartHumansKineticsMembrane PotentialsOocytesPhenethylaminesPotassium Channel BlockersPotassium ChannelsPotassium Channels, Voltage-GatedSulfonamidesTrans-ActivatorsTranscriptional Regulator ERGXenopus

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12065732

Citation

Park, Jin-Bong, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 302, no. 1, 2002, pp. 314-9.
Park JB, Choe H, Lee YK, et al. 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. J Pharmacol Exp Ther. 2002;302(1):314-9.
Park, J. B., Choe, H., Lee, Y. K., Ha, K. C., Rhee, K. S., Ko, J. K., Joo, C. U., Chae, S. W., & Kwak, Y. G. (2002). 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. The Journal of Pharmacology and Experimental Therapeutics, 302(1), 314-9.
Park JB, et al. 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. J Pharmacol Exp Ther. 2002;302(1):314-9. PubMed PMID: 12065732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Park,Jin-Bong, AU - Choe,Han, AU - Lee,Yu-Kyung, AU - Ha,Ki-Chan, AU - Rhee,Kyoung-Suk, AU - Ko,Jae-Ki, AU - Joo,Chan-Uhng, AU - Chae,Soo-Wan, AU - Kwak,Yong-Geun, PY - 2002/6/18/pubmed PY - 2002/7/13/medline PY - 2002/6/18/entrez SP - 314 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 302 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12065732/Open_channel_block_by_KCB_328_[1__2_amino_4_methanesulfonamidophenoxy__2_[N__34_dimethoxyphenethyl__N_methylamino]ethane_hydrochloride]_of_the_heterologously_expressed_human_ether_a_go_go_related_gene_K+_channels_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12065732 DB - PRIME DP - Unbound Medicine ER -