Methods: Human ether-à-go-go related gene (hERG), KCNQ and Kv1.2 channels were expressed in CHO cells. The delayed rectifier potassium current (IK) was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-100 Rapid Solution Changer.
Results: Both DC031050 and dofetilide potently inhibited hERG currents with IC50 values of 2.3±1.0 and 17.9±1.2 nmol/L, respectively. DC031050 inhibited the IK current with an IC50 value of 2.7±1.5 μmol/L, which was >1000 times the concentration required to inhibit hERG current. DC031050 at 3 μmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of IK, or the rate of IK from inactivation. Intracellular application of DC031050 (5 μmol/L) was insufficient to inhibit IK. DC031050 up to 10 μmol/L had no effects on KCNQ2 and Kv1.2 channel currents.
Conclusion: DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.