Optically Active Mexiletine Analogues as Stereoselective Blockers of Voltage-Gated Na⁺ Channels

Abstract

Optically active mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenylethanamine [(R)-3b], was 27-fold more potent than (R)-mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.

Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs

“…1), markedly enhanced drug potency. 17 The sum of these findings prompted us to synthesize two new compounds (2 and 3, Fig. 1) in order to better explore the importance of the position of the stereogenic center relative to the terminal amino group of Mex on the homologated alkyl chain of 1.…”

Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

“…[28][29][30] In the past years, a series of selective serotonine (5-HT)-reuptake inhibitor (SSRI) antidepressants (e.g. Fluoxetine and Paroxetine) and selective norepinephrine (NE)-reuptake inhibitor antidepressants (e.g.…”

Stereoselective synthesis of mexiletine and structural analogs with chiral tert-butanesulfinamide

“…4 More recently, several mexiletine analogs have been identified that have greater potency for inhibition of Na + channel currents with a stereochemical preference for (R)-mexiletine analogs. 5 Several approaches to the preparation of mexiletine enantiomers have been reported. Chiral resolution of mexiletine was first reported using a chiral co-crystallization method, 4,6 and later by derivatization of the racemate with a removable chiral auxiliary.…”

“…9 Among de novo syntheses, Franchini and colleagues have reported a number of approaches to synthesize enantiomers of mexiletine or its metabolites by stereospecific transformations of chiral precursor molecules. 5,10 In one example, ring-opening of (R)-or (S)-propylene oxide with xylenol provided a chiral alcohol that was subsequently converted to individual enantiomers of mexiletine. 11 Sasikumar and co-workers have applied Jacobsen's hydrolytic kinetic resolution to a racemic epoxide precursor of mexiletine and the resolved chiral epoxide was subsequently converted to (R)-mexiletine.…”