Deprenyl, a specific monoamine oxidase-B inhibitor (MAO-B) has been shown to prevent MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) induced neuronal cell death and thus over coming MPTP induced Parkinson's disease. MPTP is converted to MPP+ (1-methyl-4-phenyl-pridinium), which is responsible for cell death. Last year we showed that deprenyl completely prevented MPTP induced cell death. Last year we showed that deprenyl completely prevented MPTP induced cell death in cultured hepatocytes without any affect on MPP+-induced cell death. We have now investigated the structural requirement of deprenyl to induce this effect both in vivo and in vitro. Three structural analogs of deprenyl developed in Hungary in Dr. Knoll's Institute were used in the study. of all the analogs, J508 was found to be most active in preventing hepatocytes cell death induced by MPTP. The inhibitory effect of all deprenyl analogs depended on the concentrations of MPTP employed. At concentration of MPTP below 0.5 mM, all three analogs completely prevented MPTP induced cell death. At 0.5 mM MPTP, however, the IC50 for inhibition cell death by the inhibitors were: deprenyl 11 MuM, TZ650, 3 MuM; U1424, 2 MuM; and J508, 0.5 MuM. These drugs were tested in vivo in pigmented mice against MPTP induced striatal dopamine depletion at doses of 1 and 3 mg/kg. All analogs of deprenyl completely prevented the depletion. For deprenyl, ED50 was about 0.3 mg/kg. It may be possible to develop deprenyl analogs that are more potent than deprenyl in humans in preventing development of Parkinson's disease.
