Identification of A Potent Herg Channel Activator with A Novel Mechanism of Action

hERG potassium channels are an important component of cardiac action potential repolarization, and loss of function mutations of hERG channels prolong the cardiac ECG QT interval. Long QT Syndrome is associated with cardiac rhythm disorders, including torsades de pointes, which can degenerate into lethal ventricular fibrillation. In this study, we report the discovery of a potent hERG activator (Compound 1). Using whole cell patch-clamp studies of recombinant hERG expressed in HEK293 cells, we found that 3 μM Compound 1 increased hERG current amplitude more than 10-fold. This increase was reversed by the hERG blocker E4031(1 μM). Enhancement of hERG was steeply concentration dependent (EC50 0.5 ± 0.1 μM, Hill slope 3.3 ± 0.2). The observed increase in amplitude was primarily due to removal of channel inactivation. The compound also produced a hyperpolarizing shift in the voltage dependence of channel activation at high concentrations and a modest slowing of deactivation. In isolated guinea pig ventricular myocytes, Compound 1 produced a concentration-dependent shortening of action potential duration (>70%, 3 μM) that was prevented by pre-incubation with E4031. In conclusion, we have identified a novel activator of hERG potassium channels. This compound may provide a useful tool for further biophysical characterization of hERG channels and investigation of cardiac electrophysiology.