RESUMO
R-(-)-Deprenyl (Selegiline) represents one of the drugs currently used for the treatment of Parkinson's disease. This compound was shown to protect neurons or glias from programmed cell death in a variety of models. The mechanism of action of neuroprotection as well as inhibition of apoptosis remains elusive. CGP 3466 is a structurally related analog of R-(-)-deprenyl that exhibits virtually no monoamine oxidase type B inhibiting activity but is neuroprotective in the picomolar concentration range. We showed specific binding of CGP 3466 to glyceraldehyde-3-phosphate dehydrogenase by affinity binding, by affinity labeling, and by means of BIAcore(R) technology. Apoptosis assays based on the human neuroblastoma cell line PAJU established the importance of this interaction for mediating drug-induced inhibition of programmed cell death.
Assuntos
Apoptose/efeitos dos fármacos , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Oxepinas/farmacologia , Selegilina/farmacologia , Animais , Antiparkinsonianos/farmacologia , Técnicas Biossensoriais , Encéfalo/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/genética , Humanos , Microscopia de Fluorescência , Estrutura Molecular , Músculos/enzimologia , Neuroblastoma/metabolismo , Fármacos Neuroprotetores , Oligonucleotídeos Antissenso/farmacologia , Doença de Parkinson/tratamento farmacológico , Marcadores de Fotoafinidade/metabolismo , Propilaminas/farmacologia , Ligação Proteica/fisiologia , Coelhos , Ratos , Selegilina/análogos & derivadosRESUMO
Immobilized compounds for BIAcore studies and affinity precipitation as well as a fluorescent-labeled compound were prepared in order to identify the molecular target of the anti-apoptotic, neurorescuing compound CGP 3466 (N-methyl-N-propargyl-10-aminomethyl-dibenzo[b,f]oxepin).
