RESUMO
The discovery, synthesis and structure-activity studies of a novel series of 2-arylpyrimidin-4-ones as CRF-1 receptor antagonists is described. These compounds are structurally simple and display appropriate physical properties for CNS agents
Assuntos
Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Fenômenos Químicos , Físico-Química , Desenho de Fármacos , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Microssomos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
5-piperazinyl-1,2,6,7-tetrahydro-5H-azepino[3,2,1-hi]indol-4-one derivatives were designed, synthesized, and identified as a new series of mixed dopamine D(2)/D(4) receptor antagonists. This series featured a rigid tricyclic ring system as an important pharmacophore core structure for high binding affinity. Molecular modeling studies are also described.
Assuntos
Antagonistas dos Receptores de Dopamina D2 , Indóis/síntese química , Indóis/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Método de Monte Carlo , Ligação Proteica , Ensaio Radioligante , Receptores de Dopamina D4 , Relação Estrutura-AtividadeRESUMO
Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 7b. Their related synthesis was also reported.
Assuntos
Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Indóis/síntese química , Indóis/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Glicina/química , Humanos , Técnicas In Vitro , Prazosina/metabolismo , Ratos , Receptores de Dopamina D4 , Proteínas Recombinantes/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of chiral benzylpiperazinyl-1-(2,3-dihydro-indol-1-yl)ethanone derivatives were prepared and examined for their affinity at dopamine D(2) and D(4) receptors. Three compounds having D(2)/D(4) affinity ratios approximating that found for the atypical neuroleptic clozapine were further evaluated in behavioral tests of antipsychotic efficacy and motor side effects.