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10-Aminomethyldibenzo[b,f]oxepin derivatives were identi®ed to show marked effects in a survival assay of trophically-withdrawn PC12 cells.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 structureactivity relationship was established. In particular the N-methyl-N-propargylaminomethyl derivative, CGP 3466, shows neurorescuing properties at concentrations as low as 10 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 identi®ed as the putative molecular target of CGP 3466-derivatives by means of af®nity binding and photoaf®nity labeling.