RESUMO
With the significant increase of life expectancy of populations in societies today, the importance of the discovery of drugs associated with neurodegenerative diseases has emerged. Therefore, neurodegenerative diseases are an important topic in Medicinal Chemistry. Although drug discovery is considered a complex and slow process, new approaches and methods have been developed with the intention of finding new chemical entities in more efficient ways. This work provides a review of virtual methodologies applied in drug discovery and especially a new model for the prediction of MAO-A inhibitors using a multi-target QSAR methodology. This model involves a mixed approach containing simple descriptors based on atom-centered fragments and functional groups (DRAGON) and topological substructural molecular design descriptors (MODESLAB). This unified multi-species QSAR model was validated through a virtual screening of a new series of oxoisoaporphine derivatives, taking into account the information in the calculated fragmental contributions. Therefore, this method represents a useful tool for the in silico screening of MAO-A inhibitors.
Assuntos
Desenho de Fármacos , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Relação Quantitativa Estrutura-Atividade , Animais , Desenho Assistido por Computador , Humanos , Doenças Neurodegenerativas/enzimologiaRESUMO
AIMS: To evaluate the central nervous pharmacological profile of 4-propyl-2H-benzo[h]-chromen-2-one (FCS-304) in ICR mice and its monoamine oxidase inhibitor activity. MAIN METHODS: FCS-304 was evaluated in screening test of central nervous system in ICR mice and against MAO activity. KEY FINDINGS: FCS-304 (25-200mg/Kg, p.o.) significantly reduced immobility time during the forced swimming test (FST) and tail suspension test (TST), but did not show effects in the rota-rod tests, maximal electroshock seizures (MES), pentylenetetrazole seizures, light-dark box, barbiturate sleeping time and cold plate tests. Furthermore, FCS-304 inhibited monoamine oxidase A (MAO-A) with IC50: 2.28+/-0.15microM, but not MAO-B. SIGNIFICANCE: These results suggest that FCS-304 could elicit antidepressant effects related to MAO-A inhibitory activity.
Assuntos
Antidepressivos/farmacologia , Cromonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacosRESUMO
Hydralazine is a hydrazine derivative used clinically as a vasodilator and antihypertensive agent. Despite numerous studies with the drug, its mechanism of action has remained unknown; guanylate cyclase activation and release of endothelial relaxing factors are thought to be involved in its vasodilator effect. Other hydrazine derivatives are known to stimulate guanylate cyclase and could therefore share the vasodilator activity of hydralazine, although such possibility has not been assessed systematically. In the present study, hydralazine, hydrazine, phenylhydrazine, and isoniazid were evaluated for vascular smooth muscle relaxation in rat aortic rings with and without endothelium, as well as after incubation with the guanylate cyclase inhibitor methylene blue. They were also tested for enhancement of cyclic guanosine monophosphate (cGMP) production by cultured rat aortic smooth muscle cells and for hypotension in the anesthetized rat. All hydrazines relaxed aortic rings, an action unaffected by endothelium removal and, in all cases except hydralazine, antagonized by methylene blue. Only phenylhydrazine increased cGMP production and only hydralazine markedly lowered blood pressure. It was concluded that hydralazine vascular relaxation is independent of endothelium and is not related to guanylate cyclase activation. The other hydrazines studied also elicit endothelium-independent relaxation, but the effect is related to guanylate cyclase. The marked hypotensive effect of hydralazine contrasts with its modest relaxant activity and is not shared by the other hydrazines. The fact that hydrazine and isoniazid produce methylene blue-sensitive relaxation, yet do not enhance cGMP production suggests the need for activating factors present in aortic rings but not in isolated cells.