Ranolazine inhibition of hERG potassium channels: Drug-pore interactions and reduced potency against inactivation mutants

The antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/I-Kr potassium channel, shows promise as an antiarrhythmic agent This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low potency, structurally similar comparator. Recordings of hERG current (I-hERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels. Docking simulations were performed using homology models built on MthK and KvAP templates. In conventional voltage clamp, ranolazine inhibited I-hERG with an IC50 of 8.03 mu M; peak IhERG during ventricular action potential clamp was inhibited similar to 62% at 10 mu M. The IC50 values for ranolazine inhibition of the S620T inactivation deficient and N588K attenuated inactivation mutants were respectively similar to 73-fold and similar to 15-fold that for WT I-hERG. Mutations near the bottom of the selectivity filter (V625A, S624A, T623A) exhibited IC(50)s between similar to 8 and 19-fold that for WT I-hERG, whilst the Y652A and F656A S6 mutations had IC(50)s similar to 22-fold and 53-fold WT controls. Low potency lidocaine was comparatively insensitive to both pore helix and S6 mutations, but was sensitive to direction of K+ flux and particularly to loss of inactivation, with an IC50 for S620T-hERG similar to 49-fold that for WT I-hERG. Docking simulations indicated that the larger size of ranolazine gives it potential for a greater range of interactions with hERG pore side chains compared to lidocaine, in particular enabling interaction of its two aromatic groups with side chains of both Y652 and F656. The N588K mutation is responsible for the SQT1 variant of short QT syndrome and our data suggest that ranolazine is unlikely to be effective against I-Kr/hERG in SQT1 patients. (C) 2014 The Authors. Published by Elsevier Ltd.