OXIDATION-PRODUCTS ARISING FROM THE ACTION OF MONOAMINE-OXIDASE-B ON 1-METHYL-4-BENZYL-1,2,3,6-TETRAHYDROPYRIDINE, A NONNEUROTOXIC ANALOG OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE

1-Methyl-4-benzyl-1,2,3,6-tetrahydropyridine (MBzTP), an analogue of t he neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, despite it s rapid oxidation by monoamine oxidase B (MAO B), is not neurotoxic. T he pyridinium expected to arise from the four-electron oxidation of MB zTP inhibits mitochondrial respiration and the oxidation of NADH in in ner membranes and is only moderately less inhibitory than 1-methyl-4-p henylpyridinium. It is also a competitive inhibitor of dopamine uptake by the dopamine transporter and hence likely to be taken up into neur ons, despite its relatively high K-i value (K-i = 21 mu M). Incubation of MBzTP with purified MAO B yields first the dihydropyridinium form, then a mixture of the pyridinium form and another unidentified produc t, in proportions that depend on the concentrations of MAO B and oxyge n. At low MAO B concentration and moderate oxygen concentration, nonen zymatic formation of the unidentified product predominates. The lack o f neurotoxicity of MBzTP appears to be due to the oxidative destructio n of the dihydropyridine and consequent failure of accumulation of 1-m ethyl-4-benzylpryidinium.