RESUMO
A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicinérgicos/farmacologia , Glicina/antagonistas & inibidores , Indóis/farmacologia , Animais , Sítios de Ligação , Ligação Competitiva , Ácidos Carboxílicos , Córtex Cerebral/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Glicina/metabolismo , Glicinérgicos/síntese química , Glicinérgicos/química , Glicinérgicos/metabolismo , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , N-Metilaspartato/farmacologia , Ratos , Receptores de Glutamato/metabolismo , Relação Estrutura-Atividade , Estricnina/farmacologiaRESUMO
A library of 80 analogues of the antibacterial compound mureidomycin was prepared using solid-phase chemistry techniques.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Técnicas de Química Combinatória , Testes de Sensibilidade Microbiana , Nucleosídeos/síntese química , Nucleosídeos/química , Nucleosídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
2,3-Dihydro-6,7-dichloro-pyrido[2,3-b]pyrazine-8-oxide was synthesized and evaluated for in vitro/in vivo antagonistic activity at the strychnine insensitive glycine binding site on the NMDA receptor revealing it to be a useful tool to evaluate the effectiveness of glycine antagonists in vivo.
Assuntos
Óxidos N-Cíclicos/farmacologia , Glicina/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Pirazinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Óxidos N-Cíclicos/síntese química , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicina/efeitos dos fármacos , Ácido Cinurênico/análogos & derivados , Ácido Cinurênico/farmacologia , Camundongos , Atividade Motora/efeitos dos fármacos , N-Metilaspartato , Pirazinas/síntese química , Ratos , Convulsões/prevenção & controle , Comportamento Estereotipado/efeitos dos fármacos , Estricnina/farmacologiaRESUMO
A novel series of indole-2-carboxylate analogues of GV150526 (1) in which the propenoic double bond was substituted with different "probes" or replaced by a isosteric cyclopropyl moiety were synthesized and evaluated for their affinity profile in order to obtain further information on the pharmacophoric model of the glycine binding site associated to the NMDA receptor.