The inhibitory effects of DC031050, a class III antiarrhythmic agent with high selectivity for hERG channels, on three neuronal potassium channels

Aim: This study was conducted to test the selectivity of a class III antiarrhythmic agent, DC031050, on cardiac hERG and neuronal potassium channels. Methods: Whole-cell voltage patch clamp was used. Results: We previously reported that DC031050, a derivative of dofetilide, exhibited more potent biological activity than its leading compound, dofetilide. Here, we show that DC031050 selectively inhibits the hERG (the human Ether-à-go-go Related Gene) potassium channel with an IC50 of 2.3 nmol/L. We also evaluated the effects of DC031050 on three types of neuronal potassium currents: KCNQ2, Kv1.2 and the delayed rectifier potassium current (IK). Whereas DC031050 exerts an inhibitory action on IK with an IC50 value of 2.7 μmol/L, which is >1000 times the concentration required to inhibit hERG channels, it elicits no effects on either KCNQ2 or Kv1.2 channels. The high selectivity of DC031050 offers a broad concentration range for the selective therapeutic inhibition of the hERG channel without affecting other non-cardiac potassium channels. Conclusion: DC031050 is a highly selective hERG potassium channel blocker that demonstrates a substantial safety margin of activity over neuronal potassium channels and thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.