Inhibition of rat brain monoamine oxidase by some analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion.

To clarify the essential chemical structures of the neurotoxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product, 1-methyl-4-phenylpyridinium ion (MPP+), that govern nigrostriatal dopamine neuron toxicity, interactions of several structurally related compounds of MPTP or MPP+ with monoamine oxidase (MAO) in rat forebrain homogenates were studied. Of the compounds tested, 4-phenyl-1,2,3,6-tetrahydropyridine (PTP), 4-phenylpyridine and 4-phenylpiperidine strongly and dose-dependently inhibited MAO-A and -B activity. Inhibition of PTP and 4-phenylpiperidine was MAO-A-selective, while that by 4-phenylpyridine was MAO-B-selective. Of these 3 compounds, only PTP time-dependently inhibited MAO-B, but not -A. Without preincubation, the modes of inhibition of MAO-A and -B by PTP were competitive. After 1 h preincubation, the mode of MAO-B inhibition changed to non-competitive, while inhibition of -A remained unchanged. PTP was oxidized by MAO-B, but not by -A, under these conditions. In contrast, 4-phenylpyridine and 4-phenylpiperidine were not substrates for either form of MAO in rat forebrain homogenates. These results, along with the other observations, indicate that PTP may essentially cause a neurotoxic effect on the nigrostriatal dopamine pathway.