Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine

摘要: Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and relieve neuropathic pain. The present study aims at investigating direct blockade hERG potassium by mexiletine metabolite m-hydroxymexiletine (MHM). Our data show that inhibits time- voltage-dependent manner, with an IC50 3.7 ± 0.7 μmol/L. Analysis initial onset current inhibition during depolarizing test pulse indicates binds preferentially open state channel. Looking for possible alternative, we (MHM), minor recently reported be as active parent compound arrhythmia animal model, weaker compared (IC50 = 22.4 ± 1.2 μmol/L). aromatic residues located S6 helix (Tyr652 Phe656) are crucial binding different affinities MHM interpreted modeling their corresponding interactions through ab initio calculations. simulations demonstrate introduction hydroxyl group on meta-position portion weakens interaction drug xylyloxy moiety Tyr652. These results provide further insights into molecular basis drug/hERG and, agreement previously clofilium ibutilide analogs, support possibility reducing potency related toxicity modifying pattern substitution clinically relevant compounds.