title: Biophysical characterization of the new human ether-a-go-go-related gene channel opener NS3623 [N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl)urea].
abstract: Within the field of new antiarrhythmic compounds, the interesting idea of activating human ether-a-go-go-related gene (HERG1) potassium channels has recently been introduced. Potentially, drugs that increase HERG1 channel activity will augment the repolarizing current of the cardiac myocytes and stabilize the diastolic interval. This may make the myocardium more resistant to events that cause arrhythmias. We here present the compound N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl)urea (NS3623), which has the ability to activate HERG1 channels expressed in Xenopus laevis oocytes with an EC50 value of 79.4 microM. Exposure of HERG1 channels to NS3623 affects the voltage-dependent release from inactivation, resulting in a half-inactivation voltage that is rightward-shifted by 17.7 mV. Moreover, the compound affects the time constant of inactivation, leading to a slower onset of inactivation of the macroscopic HERG1 currents. We also characterized the ability of NS3623 to increase the activity of different mutated HERG1 channels. The mutants S620T and S631A are severely compromised in their ability to inactivate. Application of NS3623 to any of these two mutants did not result in increased HERG1 current. In contrast, application of NS3623 to the mutant F656M increased HERG1 current to a larger extent than what was observed with wild-type HERG1 channels. Because the amino acid F656 is essential for high-affinity inhibition of HERG1 channels, it is concluded that NS3623 has a dual mode of action, being both an activator and an inhibitor of HERG1 channels. Finally, we show that NS3623 has the ability to shorten action potential durations in guinea pig papillary muscle.
authors.affiliation: NeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
authors.forename: Rie Schultz
authors.initials: RS
authors.lastname: Hansen
authors.forename: Thomas Goldin
authors.initials: TG
authors.lastname: Diness
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
mesh_terms: D000818:Animals; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects; D010210:Papillary Muscles / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; C423868:NS 3623; D010671:Phenylurea Compounds; D013777:Tetrazoles