Homologation of mexiletine alkyl chain and stereoselective blockade of skeletal muscle sodium channels.
The optical isomers (-)-(S)- and (+)-(R)-3-(2, 6-dimethylphenoxy)-2-methyl-1-propanamine (Me2), homologues of the antiarrhythmic and antimyotonic drug mexiletine (Mex), were synthesized and assayed as new potential antimyotonic agents. As observed with Mex, Me2 exhibits an enantioselective behaviour. Tests carried out on sodium currents of single muscle fibres of Rana esculenta demonstrated that (-)-(S)- and (+)-(R)-Me2 were less potent than Mex in producing tonic block, but showed a higher use-dependent block. (-)-(S)-Me2 and (-)-(R)-Mex were also used to study the excitability of muscle fibres of myotonic ADR mice, a phenotype of a recessive form of low G(Cl) myotonia. (-)-(S)-Me2 reduced spontaneous discharges and after discharges better than (-)-(R)-Mex in agreement with the use-dependent block of sodium currents.
Duranti
A
A
Istituto di Chimica Farmaceutica e Tossicologica, Facoltà di Farmacia, Piazza del Rinascimento 6, Università degli Studi di Urbino, 61029, Urbino, Italy.
Franchini
C
C
Lentini
G
G
Loiodice
F
F
Tortorella
V
V
De Luca
A
A
Pierno
S
S
Conte Camerino
D
D
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry; D004553:Electric Conductivity; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008817:Mice, Mutant Strains; D015394:Molecular Structure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology*; D009222:Myotonia / Q000188:drug therapy* / Q000503:physiopathology; D011893:Rana esculenta; D026941:Sodium Channel Blockers; D013237:Stereoisomerism
C409486:3-(2,6-dimethylphenoxy)-2-methyl-1-propanamine; D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D008801:Mexiletine