title: N-aryl-2,6-dimethylbenzamides, a new generation of tocainide analogues as blockers of skeletal muscle voltage-gated sodium channels.
abstract: On the basis of a 3D-QSAR study, a new generation of tocainide analogues were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. Data obtained by screening new compounds by means of Hille-Campbell Vaseline gap voltage-clamp recordings showed that the elongation of the alkyl chain and the introduction of lipophilic and sterically hindered groups on the amino function enhance both potency and use-dependent block. The results provide additional indications about the structural requirement of pharmacophores for further increasing potency and state-dependent block and allowed us to identify a new tocainide analogue (6f) with a favorable pharmacodynamic profile to be proposed as a valid candidate for studies aimed at evaluating its usefulness in the treatment of myotonias.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, ‡Sezione di Farmacologia, Università degli Studi di Bari "Aldo Moro" , via E. Orabona n. 4, 70126 Bari, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Muraglia
authors.forename: Michela
authors.initials: M
authors.lastname: De Bellis
authors.forename: Alessia
authors.initials: A
authors.lastname: Catalano
authors.forename: Alessia
authors.initials: A
authors.lastname: Carocci
authors.forename: Carlo
authors.initials: C
authors.lastname: Franchini
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fortugno
authors.forename: Carlo
authors.initials: C
authors.lastname: Bertucci
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desaphy
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
authors.forename: Diana
authors.initials: D
authors.lastname: Conte Camerino
authors.forename: Filomena
authors.initials: F
authors.lastname: Corbo
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002846:Chromatography, Affinity; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects; D013329:Structure-Activity Relationship; D016677:Tocainide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; C000588584:N-(2,6-dimethylphenyl)-3-((naphthalen-1-ylmethyl)amino)butanamide; D012709:Serum Albumin; D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; D016677:Tocainide