Stereospecific synthesis of "para-hydroxymexiletine" and sodium channel blocking activity evaluation.
Both enantiomers of "para-hydroxymexiletine" (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)- and (S)-PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na(+) channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4-position, as in PHM, reduced potency with respect to mexiletine in reducing I(Na max). However, PHM showed clear use-dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use-dependent block. Chirality 16:72-78, 2004.
Catalano
Alessia
A
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Bari, Italy.
Carocci
Alessia
A
Fracchiolla
Giuseppe
G
Franchini
Carlo
C
Lentini
Giovanni
G
Tortorella
Vincenzo
V
De Luca
Annamaria
A
De Bellis
Michela
M
Desaphy
Jean-Francois
JF
Conte Camerino
Diana
D
D000818:Animals; D001001:Anura; D020128:Inhibitory Concentration 50; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013237:Stereoisomerism
D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine; C045808:4-hydroxymexiletine