RESUMO
Two isomers of the hexahydro-tetraazaacenaphthylene templates (1 and 2) are presented as novel, potent, and selective corticotropin releasing factor-1 (CRF1) receptor antagonists. In this paper, we report the affinity and SAR of a series of compounds, as well as pharmacokinetic characterization of a chosen set. The anxiolitic activity of a selected example (2ba) in the rat pup vocalization model is also presented.
Assuntos
Acenaftenos/farmacologia , Acenaftenos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Acenaftenos/síntese química , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Pectin methylesterases catalyse the demethylesterification of cell wall polygalacturonans. In dicot plants, these ubiquitous cell wall enzymes are involved in important developmental processes including cellular adhesion and stem elongation. Here, I highlight recent studies that challenge the accepted views of the mechanism and function of pectin methylesterases, including the co-secretion of pectins and pectin methylesterases into the apoplasm, new action patterns of mature pectin methylesterases and a possible function of the pro regions of pectin methylesterases as intramolecular chaperones.
Assuntos
Arabidopsis/enzimologia , Hidrolases de Éster Carboxílico/fisiologia , Pectinas/metabolismo , Fenômenos Fisiológicos Vegetais , Arabidopsis/química , Cálcio/farmacologia , Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/genética , Parede Celular/química , Parede Celular/enzimologia , Complexo de Golgi/química , Complexo de Golgi/enzimologia , Modelos Moleculares , Chaperonas Moleculares/fisiologia , Família Multigênica , Pectinas/química , Conformação ProteicaRESUMO
Six males and one female with chronic tic disorders, whose ages ranged from 12 to 31 years, were evaluated before treatment, after 1 month on placebo, after a single 10 mg nifedipine dose (three patients), and monthly while on flunarizine 10-15 mg (mean dose of 13 mg). None of the patients receiving nifedipine improved, but treatment with flunarizine significantly decreased both motor and phonic tic severity and frequency in all but one patient. Side effects included mild transient headaches in one patient, depression in one, and bradykinesia in two. Although a double-blind study is essential to validate our findings, results suggest that flunarizine is a useful drug in the treatment of Gilles de la Tourette syndrome.