Résumé :
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Mexiletine (Mex) and tocainide (Toc) are two sodium channel blockers marketed as class IB antiarrhythmic drugs and used off label as antimyotonic drug. In particular, Mex is considered as the first choice drug by many and a clinical trial is going on to validate its use in myotonic patients. Unfortunately, Mex was recently withdrawn from the market except in Japan, whereas use of Toc is limited by hematologic toxicity.In the present study, we rationally designed new Mex and Toc derivatives and test these compounds on voltage-gated sodium currents using patch-clamp method applied to HEK293 cells expressing the skeletal muscle (hNav1.4) or cardiac (hNav1.5) sodium channel subtypes.On the basis of previous structure-activity studies, we identified the N-benzylated beta-proline Toc derivative, To10, as a very strong use-dependent blocker of skeletal muscle sodium channels. Two new compounds were obtained by eliminating the rigidity of the proline cycle (To040) or increasing the lipophilicity at the benzyl location (To042). The first maneuver had no significant effect on sodium channel blockade, whereas the substitution of naphtyl for benzyl in To042 increased compound efficacy by 5 times. The half-maximum concentration for use-dependent inhibition of hNav1.4 sodium currents by To042 was minor to 1 ?M, compared to 5 ?M for To10 and 180 ?M for Toc. Tonic and use-dependent effects of To040 and To042 were greatly attenuated by the F1586C mutation in hNav1.4, suggesting that the compounds bind to the "classic" local anesthetic receptor.Mexiletine was modified by introducing an hydroxyl group on the aromatic moiety in ortho, meta, and para positions. The ortho and para derivatives were less potent than Mex in blocking hNav1.4 currents, whereas, quite surprisingly, the effects of meta-hydroxymexiletine on hNav1.4 and hNav1.5 channels were quite similar to Mex. The less lipophilic, the less efficacious and use-dependent was the compound. The compounds were also assayed on the F1586C hNav1.4 mutant to get further insight in the molecular interactions at the local anesthetic receptor. The meta-hydoxy derivative of mexiletine may be of interest for therapy of myotonia or cardiac arrhythmia, because its reduced lipophilicity may limit its access to the central nervous system thereby reducing central side effects, whereas it conserves the same activity as mexiletine on peripheral sodium channels. Supported by AFM (grant #15020).
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