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 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 synthesis of a novel covalently immobilized crown ether based potassium ionophore is presented. Apart from previously proposed methods for the preparation of PVC linked ionophores based on the chemical modification of functionalized PVC polymers, the hereby proposed procedure involves the direct copolymerization of a suitable derivative of the bis-crown ether type potassium ionophore (BME 44) and vinyl chloride monomer. The analytical performance of the potentiometric ion selective electrodes incorporating the PVC bound ionophore were optimized and determined. Compared with electrodes based on other bis-crown ether type immobilized potassium selective ionophores a slightly improved logK(K, Na)(Pot) and a longer lifetime was found. Spectral imaging and chronoamperometry were used to study the mobility of different bis-crown ether derivatives in plasticized PVC membranes.
Assuntos
Ionóforos/síntese química , Potássio , Éteres de Coroa , Eletroquímica , Ionóforos/química , Cloreto de PolivinilaRESUMO
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.