RESUMO
A structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channel blockers that were highly selective over L-type calcium channel blockers. Among the tested compounds, (+)-4-(3,5-dichloro-4-methoxy-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-cinnamyl ester was found to be an effective and selective N-type calcium channel blocker with oral analgesic potential.
Assuntos
Analgésicos/química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/química , Ácidos Carboxílicos/química , Di-Hidropiridinas/química , Administração Oral , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Formaldeído/toxicidade , Medição da Dor/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
An efficient asymmetric synthesis of 1,4-dihydropyridine derivatives is described. The key step is the stereoselective Michael addition using t-butyl ester of L-valine as a chiral auxiliary to achieve good ee (>95% for all the tested experiments) and moderate yield. With this method, (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid cinnamyl ester was obtained and was characterized as a promising N-type calcium channel blocker with improved selectivity over L-type compared to its (-)- and racemic isomers.
Assuntos
Canais de Cálcio Tipo N/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Animais , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Humanos , Éteres Metílicos/síntese química , Éteres Metílicos/química , Éteres Metílicos/farmacologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In order to find an injectable and selective N-type calcium channel blocker, we have performed the structure-activity relationship (SAR) study on the 2-, 5-, and 6-position of 1,4-dihydropyridine-3-carboxylate derivative APJ2708 (2), which is a derivative of Cilnidipine and has L/N-type calcium channel dual inhibitory activities. As a consequence of the optimization, 6-dimethylacetal derivative 7 was found to have an effective inhibitory activity against N-type calcium channels with more than 170-fold lower activity for L-type channel compared to that of APJ2708.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Di-Hidropiridinas/síntese química , Humanos , Ratos , Solubilidade , Relação Estrutura-Atividade , Água/químicaRESUMO
Antiallergic drug cyproheptadine (Cyp) is known to have inhibitory activities for L-type calcium channels in addition to histamine and serotonin receptors. Since we found that Cyp had an inhibitory activity against N-type calcium channel, Cyp was optimized to obtain more selective N-type calcium channel blocker with analgesic action. As a consequence of the optimization, we found 13 with potent N-type calcium channel inhibitory activity which had lower inhibitory activities against L-type calcium channel, histamine (H1), and serotonin (5-HT2A) receptors than those of Cyp. 13 showed an oral analgesic activity in rat formalin-induced pain model.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/efeitos dos fármacos , Ciproeptadina/análogos & derivados , Ciproeptadina/farmacologia , Desenho de Fármacos , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Linhagem Celular Tumoral , Ciproeptadina/química , Avaliação Pré-Clínica de Medicamentos , Formaldeído/química , Cobaias , Humanos , Técnicas In Vitro , Masculino , Estrutura Molecular , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Cilnidipine is a 1,4-dihydropyridine derived L/N-type calcium channel dual blocker possessing neuroprotective and analgesic effects which are related to its N-type calcium channel inhibitory activity. In order to find specific N-type calcium channel blockers with the least effects on cardiovascular system, we performed structure-activity relationship study on APJ2708, which is a derivative of cilnidipine, and found a promising N-type calcium channel blocker 21b possessing analgesic effect in vivo with a 1600-fold lower activity against L-type calcium channels than that of cilnidipine.