title: Pharmacological removal of human ether-à-go-go-related gene potassium channel inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574).
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 EC(50) value of 0.5 +/- 0.1 microM and a Hill slope (n(H)) 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 microM) 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 microM) 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 microM) 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.
authors.affiliation: Icagen, Inc., Durham, NC 27703, USA. agerlach@icagen.com
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Gerlach
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Stoehr
authors.forename: Neil A
authors.initials: NA
authors.lastname: Castle
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists* / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; C063968:E 4031