RESUMO
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.
Assuntos
Antiarrítmicos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Tocainide/análogos & derivados , Tocainide/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Antiarrítmicos/síntese química , Cromatografia de Afinidade , Cromatografia Líquida de Alta Pressão , Humanos , Modelos Moleculares , Técnicas de Patch-Clamp , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Ratos , Albumina Sérica/metabolismo , Canais de Sódio/efeitos dos fármacos , Relação Estrutura-Atividade , Tocainide/síntese químicaRESUMO
1-Benzyl-N-(2,6-dimethylphenyl)piperidine-3-carboxamide and 4-benzyl-N-(2,6-dimethylphenyl)piperazine-2-carboxamide, two conformationally restricted analogues of tocainide, were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. They showed, with respect to tocainide, a marked increase in both potency and use-dependent block.
Assuntos
Músculo Esquelético/efeitos dos fármacos , Miotonia , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/farmacologia , Tocainide/síntese química , Tocainide/farmacologia , Estrutura Molecular , Músculo Esquelético/metabolismo , Bloqueadores dos Canais de Sódio/química , Relação Estrutura-Atividade , Tocainide/análogos & derivados , Tocainide/químicaRESUMO
A series of the new aminoalkyl esters of chlor-, methyl- and alkoxy carbanilates was synthesized. All the compounds prepared were found to exhibit antiarrhythmic activities comparable with those of mexiletine.
