Synthesis and dihydropteridine reductase inhibitory effects of potential metabolites of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a nigrostriatal neurotoxin which can cause irreversible parkinsonism in humans and primates by selective destruction of neurons in the substantia nigra. It is possible that MPTP could be metabolized by hydroxylation of the phenyl ring and/or aromatization of its nitrogen-containing ring. Hydroxylated derivatives of 4-phenyl-1,2,3,6-tetrahydropyridine, 4-phenylpiperidine, and 4-phenylpyridine were synthesized and tested in vitro as inhibitors of dihydropteridine reductase (DHPR) from human liver and rat striatal synaptosomes. It was found that all hydroxy derivatives were about 100-10 000 times more inhibitory than MPTP to DHPR. The inhibitory potency of the hydroxylated derivatives increased with the number of hydroxyl substitutions present on the phenyl ring (catechol greater than phenol) and with oxidation of the nitrogen-containing ring (pyridine greater than tetrahydropyridine greater than piperidine).