title: Searching for new antiarrhythmic agents: evaluation of meta-hydroxymexiletine enantiomers.
abstract: Mexiletine is a very well-known class IB antiarrhythmic drug, whose enantiomers differ in both pharmacodynamic and pharmacokinetic properties, the (R)-isomer being the eutomer on experimental arrhythmias and in binding studies on cardiac voltage-gated sodium channels. meta-Hydroxymexiletine (MHM) is a minor metabolite of mexiletine, which has demonstrated to be more potent than the parent compound. Herein we report the synthesis and biological evaluation of MHM enantiomers for their potential antiarrhythmic activity. The same stereoselectivity pattern observed for mexiletine was found for MHM: the (R)-enantiomer of MHM was the eutomer on ac-arrhythmia also showing a negative inotropism higher than the one displayed by mexiletine and, at the same time, a decreased vasorelaxant activity on guinea-pig left atrium and guinea-pig ileum longitudinal smooth muscle.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona n. 4, 70126 Bari, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Catalano
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.forename: Antonia
authors.initials: A
authors.lastname: Di Mola
authors.forename: Ivana
authors.initials: I
authors.lastname: Defrenza
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Cavalluzzi
authors.forename: Matteo
authors.initials: M
authors.lastname: Micucci
authors.forename: Alessia
authors.initials: A
authors.lastname: Carocci
authors.forename: Carlo
authors.initials: C
authors.lastname: Franchini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lentini
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013237:Stereoisomerism
chemical_list: D000889:Anti-Arrhythmia Agents; C069734:3-hydroxymexiletine; D008801:Mexiletine
keywords: Antiarrhythmic drugs; Mexiletine; Sodium channel blockers; meta-Hydroxymexiletine