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.
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Authors | Marilena 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 |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 57
Issue 6
Pg. 2589-600
(Mar 27 2014)
ISSN: 1520-4804 [Electronic] United States |
PMID | 24568674
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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