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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.
AuthorsMarilena Muraglia, Michela De Bellis, Alessia Catalano, Alessia Carocci, Carlo Franchini, Antonio Carrieri, Cecilia Fortugno, Carlo Bertucci, Jean-François Desaphy, Annamaria De Luca, Diana Conte Camerino, Filomena Corbo
JournalJournal of medicinal chemistry (J Med Chem) Vol. 57 Issue 6 Pg. 2589-600 (Mar 27 2014) ISSN: 1520-4804 [Electronic] United States
PMID24568674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Arrhythmia Agents
  • N-(2,6-dimethylphenyl)-3-((naphthalen-1-ylmethyl)amino)butanamide
  • Serum Albumin
  • Sodium Channels
  • Voltage-Gated Sodium Channel Blockers
  • Tocainide
Topics
  • Animals
  • Anti-Arrhythmia Agents (chemical synthesis, pharmacology)
  • Chromatography, Affinity
  • Chromatography, High Pressure Liquid
  • Humans
  • Models, Molecular
  • Muscle, Skeletal (drug effects)
  • Patch-Clamp Techniques
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Rats
  • Serum Albumin (metabolism)
  • Sodium Channels (drug effects)
  • Structure-Activity Relationship
  • Tocainide (analogs & derivatives, chemical synthesis, pharmacology)
  • Voltage-Gated Sodium Channel Blockers (chemical synthesis, pharmacology)

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