CYTOTOXICITY OF 1-AMINO-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE AND 1-AMINO-4-PHENYLPYRIDINIUM ION, 1-AMINO ANALOGS OF MPTP AND MPP+, TO CLONALPHEOCHROMOCYTOMA PC12 CELLS

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsoni sm 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 toxic ity to clonal pheochromocytoma PC12 cells was examined using a tetrazo lium 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-met hyl analogues, only MPP+, but not MPTP, was cytotoxic. The cytotoxicit y of APTP increased with incubation time and equaled that of MPP+ afte r 72 h. It was found that APTP was oxidized to APP(+) by type A monoam ine oxidase in PC12 cells, suggesting that APP(+) itself may damage th e cells. In addition to APTP and APP(+), N-amino analogues of N-methyl isoquinolines and related derivatives were also synthesized and examin ed for their cytotoxicity to PC12 cells.