title: Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel.
abstract: Many drugs inhibit the human ether-a-go-go-related gene (HERG) cardiac K+ channel. This leads to action potential prolongation on the cellular level, a prolongation of the QT interval on the electrocardiogram, and sometimes cardiac arrhythmia. To date, no activators of this channel have been reported. Here, we describe the in vitro electrophysiological effects of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243), a novel activator of HERG. Using patch-clamp electrophysiology, we found that RPR260243 dramatically slowed current deactivation when applied to cells stably expressing HERG. The effects of RPR260243 on HERG channel deactivation were temperature- and voltage-dependent and occurred over the concentration range of 1 to 30 microM. RPR260243-modified HERG currents were inhibited by dofetilide (IC50 = 58 nM). RPR260243 had little effect on HERG current amplitude and no significant effects on steady-state activation parameters or on channel inactivation processes. RPR260243 displayed no activator-like effects on other voltage-dependent ion channels, including the closely related erg3 K+ channel. RPR260243 enhanced the delayed rectifier current in guinea pig myocytes but, when administered alone, had little effect on action potential parameters in these cells. However, RPR260243 completely reversed the action potential-prolonging effects of dofetilide in this preparation. Using the Langendorff heart method, we found that 5 microM RPR260243 increased T-wave amplitude, prolonged the PR interval, and shortened the QT interval. We believe RPR260243 represents the first known HERG channel activator and that the drug works primarily by inhibiting channel closure, leading to a persistent HERG channel current upon repolarization. Compounds like RPR260243 will be useful for studying the physiological role of HERG and may one day find use in treating cardiac disease.
authors.affiliation: Department of Medicinal Chemistry, Aventis Pharmaceuticals, Vitry-Sur-Seine, France.
authors.forename: Jiesheng
authors.initials: J
authors.lastname: Kang
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Chen
authors.forename: Hongge
authors.initials: H
authors.lastname: Wang
authors.forename: Junzhi
authors.initials: J
authors.lastname: Ji
authors.forename: Hsien
authors.initials: H
authors.lastname: Cheng
authors.forename: Josephine
authors.initials: J
authors.lastname: Incardona
authors.forename: William
authors.initials: W
authors.lastname: Reynolds
authors.forename: Fabrice
authors.initials: F
authors.lastname: Viviani
authors.forename: Michel
authors.initials: M
authors.lastname: Tabart
authors.forename: David
authors.initials: D
authors.lastname: Rampe
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008133:Long QT Syndrome; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; C000606913:KCNH2 protein, human; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011804:Quinolines; C499186:RPR260243