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 Kϩ 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 voltagedependent and occurred over the concentration range of 1 to 30 M. RPR260243-modified HERG currents were inhibited by dofetilide (IC 50 ϭ 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 voltagedependent ion channels, including the closely related erg3 K ϩ 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 M 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.

Pharmacological approach to the treatment of long and short QT syndromes

“…HERG blockade is the major determinant of drug-induced QT prolongation and TdP. The first drug in this class, RPR260243, was shown to reverse dofetilide-induced APD prolongation in guinea pig myocytes (Kang et al, 2005). More potent than the first agent, PD-118057 was found to reduce the APD of endocardial and epicardial cells and abbreviate the QT interval when infused alone in rabbit left ventricular wedge (Zhou et al, 2005).…”

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

“…Molecules activating hERG have also been found [172][173][174][175][176]. Furthermore, auxiliary subunits can also work as binding sites for some channel activators [177].…”

Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

“…RPR260243 dramatically slows current deactivation in patch-clamp experiments, and its effect is temperature and voltage dependent. Though it is a weak inhibitor of the L-type Ca 2+ channel, RPR260243 has no significant effects on the human cardiac Na + channel or the KCNQ1/KCNE1 cardiac K + channel, which are also linked with LQTS, thus showing high selectivity for hERG [22] . Interestingly, RPR260243 inhibits the erg3 channel, which is in the same family as hERG, and a single S5 residue may account for this difference in pharmacology (Thr556 in hERG, Ile558 in rERG3).…”

“…Additionally, RPR260243 enhances the delayed rectifier current in guinea pig myocytes and can, to some extent, reverse dofetilide-induced prolongation of action potential. Physiologically, it has been reported that RPR260243 can increase the T-wave amplitude, prolong the PR interval and shorten the QT interval in guinea pig hearts [22] .…”

“…However, due to the limitations of existing high throughput screening methods and difficulties in assaying the channel on a large scale, few activators have been reported. Most of the existing activators originated from combinatorial chemistry libraries, including RPR260243 [22][23][24] , PD-118057 [25] , PD-307243 [26] , NS1643 [27] , NS3623 [28] , A-935142 [29] , ICA-105574 [30] , and KB130015 [31] . Addi-www.nature.com/aps Zhou PZ et al Acta Pharmacologica Sinica npg tionally, a natural product, mallotoxin, has also been shown to activate hERG [32] .…”