title: Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use-dependent block of skeletal muscle Na(+) channels enhancing the antimyotonic activity in vivo.
abstract: 1. Searching for the structural requirements improving the potency and the stereoselectivity of Na(+) channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid alpha-proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers. 2. Their ability to block Na(+) currents, elicited from -100 to -20 mV at 0.3 Hz (tonic block) and 2-10 Hz (use-dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method. 3. The alpha-proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz-use-dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use-dependent block were reduced. 4. Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo-imidazolic derivatives markedly decreased the drug potency with respect to tocainide. 5. Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R-To5 than for R-Tocainide. 6. Thus, constraining the chiral centre of tocainide in alpha-proline cycle leads to more potent and stereoselective use-dependent Na(+) channel blockers with improved therapeutic potential.
authors.affiliation: Department of Pharmacobiology, Unit of Pharmacology, Faculty of Pharmacy, University of Bari, I-70125 Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Talon
authors.forename: A
authors.initials: A
authors.lastname: De Luca
authors.forename: M
authors.initials: M
authors.lastname: De Bellis
authors.forename: J F
authors.initials: JF
authors.lastname: Desaphy
authors.forename: G
authors.initials: G
authors.lastname: Lentini
authors.forename: A
authors.initials: A
authors.lastname: Scilimati
authors.forename: F
authors.initials: F
authors.lastname: Corbo
authors.forename: C
authors.initials: C
authors.lastname: Franchini
authors.forename: P
authors.initials: P
authors.lastname: Tortorella
authors.forename: H
authors.initials: H
authors.lastname: Jockusch
authors.forename: D
authors.initials: D
authors.lastname: Conte Camerino
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D009222:Myotonia / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D011893:Rana esculenta; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016677:Tocainide / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D016677:Tocainide