Dibenzoxepines as treatments for neurodegenerative diseases

In recent years, apoptotic cell death has been implicated with different progressive neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis or Alzheimer's disease. The hypothesis emerged, that a drug preventing apoptosis may slow or even halt the disease progression. (-)-Deprenyl was reported to rescue neurons from cell death in different in vitro and in vivo systems. However, deprenyl suffers the antagonizing actions of its major metabolites. We set up a screening for compounds with neurorescuing properties, lacking deprenyl's metabolic problems. 10-Aminomethyl-dibenzo[b,f]oxepin derivatives were identified to show marked effects in a survival assay of trophically-withdrawn PC12 cells. Dibenzo[b,f]oxepines bearing different aminomethyl sidechains and aromatic substituents were prepared in a multistep synthesis, and a structure-activity relationship was established. In particular the N-methyl-N-propargylaminomethyl derivative, CGP 3466, shows neurorescuing properties at concentrations as low as 10(-13) M in different in vitro test systems. In vivo, CGP 3466 prevents the death of dopaminergic cells in the mouse substantia nigra after MPTP-lesion. It also rescues mouse facial motor neurons after axotomy and increases the Life-span of mice with progressive motor neuronopathy. Glyceraldehyde-3-phosphate dehydrogenase was identified as the putative molecular target of CGP 3466-derivatives by means of affinity binding and photoaffinity labeling.