RESUMEN
(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.
Asunto(s)
Analgésicos/síntesis química , Bencimidazoles/síntesis química , Indoles/síntesis química , Piperazinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Calcio/metabolismo , Células Cultivadas , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Espacio Intracelular/metabolismo , Masculino , Ratones , Modelos Moleculares , Dimensión del Dolor , Técnicas de Placa-Clamp , Piperazinas/química , Piperazinas/farmacología , Prosencéfalo/citología , Prosencéfalo/metabolismo , Relación Estructura-Actividad Cuantitativa , Ensayo de Unión Radioligante , Ratas , Ratas WistarRESUMEN
A novel series of oxamides derived from indole-2-carboxamides was identified as potent NR2B selective NMDA receptor antagonists. Several members of this group showed good analgesic activity in the mouse formalin test.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , N-Metilaspartato/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of new spiro[naphto[2,1-c][2,7]naphtiridine-5,4'-piperidine] derivatives was prepared. Biochemical investigations revealed that all members of this series were potent inhibitors of both NADPH- and Fe(2+)-dependent lipid peroxidation (IC50 < 10 mumol/l) in rat brain microsomes and rat brain homogenate, respectively.
Asunto(s)
Peroxidación de Lípido/efectos de los fármacos , Naftalenos/síntesis química , Piperidinas/síntesis química , Quinolinas/síntesis química , Compuestos de Espiro/síntesis química , Animales , Química Encefálica/efectos de los fármacos , Fenómenos Químicos , Química Física , Técnicas In Vitro , Indicadores y Reactivos , Hierro/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Microsomas/efectos de los fármacos , Microsomas/metabolismo , NADP/farmacología , Naftalenos/farmacología , Piperidinas/farmacología , Quinolinas/farmacología , Ratas , Ratas Wistar , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of indole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the number and position of OH groups on the indole skeleton as well as the substitution of the piperidine ring on the biological activity of the compounds was studied.