title: Stereoselective interaction of tocainide and its chiral analogs with the sodium channels in human myoballs.
abstract: The effects of both enantiomers of tocainide and of some of its chiral analogs on the inactivation of the sodium current in human myoballs were investigated with the whole-cell recording technique. Structure and electron densities of the applied compounds were calculated and compared to the results. Both the R(-) and the S(+) enantiomers had little effect on fast inactivation determined with short prepulses according to Hodgkin and Huxley (1952; h infinity curve). When the inactivating prepulses used in this pulse protocol were prolonged to 1024 ms, both tocainide enantiomers increased inactivation severely, suggesting that the drug binds to the channel when it is in the state of intermediate inactivation (Fakler et al. 1990). Tetrodotoxin-resistant "juvenile" sodium channels were more affected than tetrodotoxin-sensitive "adult" channels. The R form was four times as effective as the S form. The compound obtained by substitution of the methyl group on the chiral centre of tocainide with a benzyl group, although in the less potent S form, affected inactivation of the juvenile sodium channels much more than the potent (R)-tocainide. Two additional substitutions, performed on the aromatic ring of tocainide, gave a compound that was most potent in shifting the inactivation curves, but without any selectivity for juvenile or adult channels.
authors.affiliation: Abteilung für Allgemeine Physiologie, Universität Ulm, Federal Republic of Germany.
authors.forename: D
authors.initials: D
authors.lastname: Tricarico
authors.forename: B
authors.initials: B
authors.lastname: Fakler
authors.forename: W
authors.initials: W
authors.lastname: Spittelmeister
authors.forename: J P
authors.initials: JP
authors.lastname: Ruppersberg
authors.forename: R
authors.initials: R
authors.lastname: Stützel
authors.forename: C
authors.initials: C
authors.lastname: Franchini
authors.forename: V
authors.initials: V
authors.lastname: Tortorella
authors.forename: D
authors.initials: D
authors.lastname: Conte-Camerino
authors.forename: R
authors.initials: R
authors.lastname: Rüdel
mesh_terms: D006801:Humans; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009132:Muscles / Q000502:physiology*; D012208:Rhabdomyosarcoma / Q000503:physiopathology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016677:Tocainide; D014407:Tumor Cells, Cultured
chemical_list: D015222:Sodium Channels; D016677:Tocainide; D008012:Lidocaine