RESUMEN
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.
Asunto(s)
Analgésicos/química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo N/química , Ácidos Carboxílicos/química , Dihidropiridinas/química , Administración Oral , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/metabolismo , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Evaluación Preclínica de Medicamentos , Formaldehído/toxicidad , Dimensión del Dolor/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Canales de Calcio Tipo N/efectos de los fármacos , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Animales , Ácidos Carboxílicos/química , Línea Celular Tumoral , Dihidropiridinas/síntesis química , Dihidropiridinas/química , Dihidropiridinas/farmacología , Humanos , Éteres Metílicos/síntesis química , Éteres Metílicos/química , Éteres Metílicos/farmacología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/metabolismo , Dihidropiridinas/química , Dihidropiridinas/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Dihidropiridinas/síntesis química , Humanos , Ratas , Solubilidad , Relación Estructura-Actividad , Agua/químicaRESUMEN
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.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/efectos de los fármacos , Ciproheptadina/análogos & derivados , Ciproheptadina/farmacología , Diseño de Fármacos , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Línea Celular Tumoral , Ciproheptadina/química , Evaluación Preclínica de Medicamentos , Formaldehído/química , Cobayas , Humanos , Técnicas In Vitro , Masculino , Estructura Molecular , Dolor/inducido químicamente , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
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.
