Further insight into the mode of action of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Chemical reactions of MPDP +, a recognized intermediate in the metabolic conversion of the neurotoxin MPTP by monoamine oxidase B into its major metabolite MPP + were studied.Addition of cyanide to MPDP + bromide in aqueous solutions afforded cyano-compound 5 which isomerized in the presence of silica gel into compound 6. Both 5 and 6 when heated yielded a third isomer 7. MPDP + bromide disproportionated into MPTP and MPP + in aqueous solution near neutral or slightly alkaline pH, a reaction which also occurred when MPDP + bromide was treated with an amine in dichloromethane solution. Disproportionation of MPDP + at physiological pH may be of biochemical significance, since formation of MPP + from MPDP + can occur non-enzymatically. MPTP, MPDP +, and MPP + inhibited dopamine uptake in rat synaptosomal preparations with I 50 values of 30, 37, and 3.4 μM, respectively. The competition of these compounds with dopamine for uptake sites in the membrane may contribute in part to the reduced levels of dopamine observed in animals treated with MPTP.