Cytotoxicity of 1-amino-4-phenyl-1,2,3,6-tetrahydropyridine and 1-amino-4-phenylpyridinium ion, 1-amino analogues of MPTP and MPP+, to clonal pheochromocytoma PC12 cells

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism in humans after its oxidation into 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase. The l-amino analogues of MPTP and MPP+, 1-amino-4-phenyl-1,2,3,6-tetrahydropyridine (APTP) and 1-amino-4-phenylpyridinium ion (APP(+)), were synthesized, and their cyto toxicity to clonal pheochromocytoma PC12 cells was examined using a tetrazolium formazan assay. After incubation for 48 and 72 h, both APP(+) and APTP were found to be cytotoxic to PC12 cells, whereas with the N-methyl analogues, only MPP+, but not MPTP, was cytotoxic. The cytotoxicity of APTP increased with incubation time and equaled that of MPP+ after 72 h. It was found that APTP was oxidized to APP(+) by type A monoamine oxidase in PC12 cells, suggesting that APP(+) itself may damage the cells. In addition to APTP and APP(+), N-amino analogues of N-methylisoquinolines and related derivatives were also synthesized and examined for their cytotoxicity to PC12 cells.