1. N-aryl-2,6-dimethylbenzamides, a new generation of tocainide analogues as blockers of skeletal muscle voltage-gated sodium channels.
- Author
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Muraglia M, De Bellis M, Catalano A, Carocci A, Franchini C, Carrieri A, Fortugno C, Bertucci C, Desaphy JF, De Luca A, Conte Camerino D, and Corbo F
- Subjects
- Animals, Anti-Arrhythmia Agents chemical synthesis, Chromatography, Affinity, Chromatography, High Pressure Liquid, Humans, Models, Molecular, Patch-Clamp Techniques, Protein Binding, Quantitative Structure-Activity Relationship, Rats, Serum Albumin metabolism, Sodium Channels drug effects, Structure-Activity Relationship, Tocainide chemical synthesis, Anti-Arrhythmia Agents pharmacology, Muscle, Skeletal drug effects, Tocainide analogs & derivatives, Tocainide pharmacology, Voltage-Gated Sodium Channel Blockers chemical synthesis, Voltage-Gated Sodium Channel Blockers pharmacology
- 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.
- Published
- 2014
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