RESUMO
(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.
Assuntos
Analgésicos/síntese química , Benzimidazóis/síntese química , Indóis/síntese química , Piperazinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Analgésicos/química , Analgésicos/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Cálcio/metabolismo , Células Cultivadas , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Espaço Intracelular/metabolismo , Masculino , Camundongos , Modelos Moleculares , Medição da Dor , Técnicas de Patch-Clamp , Piperazinas/química , Piperazinas/farmacologia , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Ratos , Ratos WistarRESUMO
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.
Assuntos
Peroxidação de Lipídeos/efeitos dos fármacos , Naftalenos/síntese química , Piperidinas/síntese química , Quinolinas/síntese química , Compostos de Espiro/síntese química , Animais , Química Encefálica/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Técnicas In Vitro , Indicadores e Reagentes , Ferro/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , NADP/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Quinolinas/farmacologia , Ratos , Ratos Wistar , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Indóis/síntese química , Indóis/farmacologia , N-Metilaspartato/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.