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 novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed.
Assuntos
Ácido Cinurênico/análogos & derivados , Ácido Cinurênico/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Sítios de Ligação , Cromatografia Líquida de Alta Pressão , Formaldeído , Indicadores e Reagentes , Ácido Cinurênico/síntese química , Espectroscopia de Ressonância Magnética , Camundongos , Medição da Dor/efeitos dos fármacos , Piperidinas/metabolismo , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
A novel series of benzimidazole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of some structural elements, like H-bond donor groups placed on the benzimidazole skeleton and the substitution pattern of the piperidine ring, on the biological activity was studied. Compound 6a showed excellent analgetic activity in the mouse formalin test following po administration.
Assuntos
Amidas/química , Amidas/farmacologia , Benzimidazóis/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Amidas/síntese química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The quest for NR2B subtype selective NMDA antagonists started almost twenty years ago. The structure of ifenprodil, the prototype of this group of compounds, inspired many medicinal chemists in several research units. Different approaches led to the identification of the pharmacophore and several distinct classes of compounds containing this pharmacophore. From these studies a few drug candidates emerged and clinical trials proved the viability of the concept. This article attempted to follow the evolution from ifenprodil, a multiple ligand, to selective NR2B antagonists.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Humanos , Relação Estrutura-AtividadeRESUMO
A novel series of indole-2-carboxamidine derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substituents on the indole skeleton as well as the substitution of the benzyl moiety on the biological activity of the compounds was studied. Compound 5a was po active in the formalin test in mouse.
Assuntos
Aminoimidazol Carboxamida/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , N-Metilaspartato/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Aminoimidazol Carboxamida/síntese química , Animais , Cálcio/metabolismo , Técnicas de Cultura de Células , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Imidazóis/síntese química , Indóis/síntese química , RatosRESUMO
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.
