Optically active mexiletine analogues as stereoselective blockers of voltage-gated Na(+) channels.
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.
Franchini
Carlo
C
Dipartimento Farmaco-Chimico and Farmaco-Biologico, Università degli Studi di Bari - Via E Orabona 4, 70125 Bari, Italy. cfranc@farmchim.uniba.it
Carocci
Alessia
A
Catalano
Alessia
A
Cavalluzzi
Maria M
MM
Corbo
Filomena
F
Lentini
Giovanni
G
Scilimati
Antonio
A
Tortorella
Paolo
P
Camerino
Diana Conte
DC
De Luca
Annamaria
A
D000818:Animals; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D011893:Rana esculenta; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C479891:2-(2-methylphenoxy)-1-phenylethanamine; D010627:Phenethylamines; D010647:Phenyl Ethers; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine