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Further insight into the mode of action of the neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)
Author(s) -
Gessnerf Wieslaw,
Brossi Arnold,
Shen Rong-sen,
Abell Creed W.
Publication year - 1985
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(85)80807-3
Subject(s) - mptp , neurotoxin , chemistry , bromide , dopamine , metabolite , stereochemistry , biochemistry , dopaminergic , biology , organic chemistry , neuroscience
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.