Abstract
Human ether-à-go-go-related gene (hERG) potassium channel activity helps shape the cardiac action potential and influences its duration. In this study, we report the discovery of 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574), a potent and efficacious hERG channel activator with a unique mechanism of action. In whole-cell patch-clamp studies of recombinant hERG channels, ICA-105574 steeply potentiated current amplitudes more than 10-fold with an EC50 value of 0.5 ± 0.1 μM and a Hill slope (nH) of 3.3 ± 0.2. The effect on hERG channels was confirmed because the known hERG channel blockers, N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide, 2HCl (E-4031) and BeKm-1, potently blocked the stimulatory effects of ICA-105574. The primary mechanism by which ICA-105574 potentiates hERG channel activity is by removing hERG channel inactivation, because ICA-105574 (2 μM) shifts the midpoint of the voltage-dependence of inactivation by >180 mV from −86 to +96 mV. In addition to the effects on inactivation, greater concentrations of ICA-105574 (3 μM) produced comparatively small hyperpolarizing shifts (up to 11 mV) in the voltage-dependence of channel activation and a 2-fold slowing of channel deactivation. In isolated guinea pig ventricular cardiac myocytes, ICA-105574 induced a concentration-dependent shortening of action potential duration (>70%, 3 μM) that could be prevented by preincubation with E-4031. In conclusion, we identified a novel agent that can prevent the inactivation of hERG potassium channels. This compound may provide a useful tool to further understand the mechanism by which hERG channels inactivate and affect cardiac function in addition to the role of hERG channels in other cell systems.
Footnotes
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.059543.
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ABBREVIATIONS:
- hERG
- human ether-à-go-go-related gene
- E-4031
- N--[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide, 2HCl
- HEK
- human embryonic kidney
- PD-118057
- 2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid
- PD-307243
- 2-[2-(3,4-dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid
- A-935142
- (4-(4-(5-trifluoromethyl-1H-pyrazol-3-yl)phenyl)cyclohexyl)acetic acid
- RPR260243
- (3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid
- NS1643
- 1,3-bis-[2-hydroxy-5-(trifluoromethyl)phenyl]urea
- NS3623
- N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N′-(3′-trifluoromethylphenyl)urea.
- Received July 16, 2009.
- Accepted October 5, 2009.
- © 2010 The American Society for Pharmacology and Experimental Therapeutics
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