RT Journal Article
SR Electronic
T1 Discovery of a Small Molecule Activator of the Human <em>Ether-a-go-go</em>-Related Gene (HERG) Cardiac K<sup>+</sup> Channel
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 827
OP 836
DO 10.1124/mol.104.006577
VO 67
IS 3
A1 Jiesheng Kang
A1 Xiao-Liang Chen
A1 Hongge Wang
A1 Junzhi Ji
A1 Hsien Cheng
A1 Josephine Incardona
A1 William Reynolds
A1 Fabrice Viviani
A1 Michel Tabart
A1 David Rampe
YR 2005
UL http://molpharm.aspetjournals.org/content/67/3/827.abstract
AB 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 μM. 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 μM 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.