title: New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse.
abstract: The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.
authors.affiliation: Unit of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, Via Orabona 4, Campus, 70125 Bari, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
authors.forename: Sabata
authors.initials: S
authors.lastname: Pierno
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desaphy
authors.forename: Fedele
authors.initials: F
authors.lastname: Natuzzi
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Didonna
authors.forename: Ermanno
authors.initials: E
authors.lastname: Ferrannini
authors.forename: Harald
authors.initials: H
authors.lastname: Jockusch
authors.forename: Carlo
authors.initials: C
authors.lastname: Franchini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lentini
authors.forename: Filomena
authors.initials: F
authors.lastname: Corbo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tortorella
authors.forename: Diana Conte
authors.initials: DC
authors.lastname: Camerino
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004576:Electromyography / Q000379:methods; D005260:Female; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D008801:Mexiletine / Q000097:blood / Q000627:therapeutic use*; D051379:Mice; D008817:Mice, Mutant Strains; D009119:Muscle Contraction / Q000187:drug effects; D020967:Myotonic Disorders / Q000097:blood / Q000188:drug therapy*; D018408:Patch-Clamp Techniques / Q000379:methods; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013997:Time Factors; D016677:Tocainide / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels; D008801:Mexiletine; D016677:Tocainide