Oxidation products arising from the action of monoamine oxidase B on 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-benzyl-1,2,3,6-tetrahydropyridine (MBzTP), an analogue of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, despite its rapid oxidation by monoamine oxidase B (MAO B), is not neurotoxic. The pyridinium expected to arise from the four-electron oxidation of MBzTP inhibits mitochondrial respiration and the oxidation of NADH in inner membranes and is only moderately less inhibitory than 1-methyl-4-phenylpyridinium. It is also a competitive inhibitor of dopamine uptake by the dopamine transporter and hence likely to be taken up into neurons, despite its relatively high Ki value (Ki = 21 microM). Incubation of MBzTP with purified MAO B yields first the dihydropyridinium form, then a mixture of the pyridinium form and another unidentified product, in proportions that depend on the concentrations of MAO B and oxygen. At low MAO B concentration and moderate oxygen concentration, nonenzymatic formation of the unidentified product predominates. The lack of neurotoxicity of MBzTP appears to be due to the oxidative destruction of the dihydropyridine and consequent failure of accumulation of 1-methyl-4-benzylpyridinium.

Molecular basis of discrepancies in neurotoxic properties among 1-methyl-4-aryl-1,2,3,6-tetrahydropyridines.

The relationship between structural specificity of the main stages of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) action and the display of parkinsonogenic properties among homologous structures in a number of 4-tolyl derivatives of MPTP has been studied. All the compounds are better substrates for monoamine oxidase (MAO) than MPTP. MAO is inactivated during the reaction according to a mechanism of irreversible inhibition by 2,3-dihydropyridinium metabolite. All the tolyl derivatives are stronger inhibitors of MAO than 1-methyl-2,3-dihydropyridinium (MPDP). A significant contribution of enzyme inhibition to the catalytic conversion of the substrate leads to the fact that substrates having equal (para isomer) or even higher (meta isomer) values of catalytic parameters are oxidized by MAO to a lesser extent than MPTP. It has been found that all 4-arylpyridiniums (final products of MATP bioconversion) competitively and reversibly inhibit [14C]dopamine (DA) uptake in mouse brain synaptosomes. Affinity toward DA transporter characterized by KI (microM) is 0.37 +/- 0.04, 0.7 +/- 0.1, 2.0 +/- 0.15, 2.0 +/- 0.35 for MPP, and its o-, m-, and p-tolyl derivatives, respectively. Joint calculation of specificity factors for the processes discussed define the following rank order for the bio-delivery of MATP's metabolic produces into DA nerve terminals: o-tolyl > MPTP >> m-tolyl > p-tolyl. The regularity revealed is in good agreement with the observed relative potency of these compounds to cause dopaminergic neurodegeneration.