Studies on the oxidation of 1,4-disubstituted-1,2,3,6-tetrahydropyridines

Interest in the parkinsonian-inducing proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine has prompted extensive studies into the oxidative pathways mediating its bioactivation to the corresponding pyridinium species, a potent inhibitor of the mitochondrial electron transport chain. The initial step in the overall reaction is the two-electron ring alpha-carbon oxidation to give the 1-methyl-4-phenyl-2,3-dihydropyridinium species, a reaction that is catalyzed by monoamine oxidase B. The same alpha-carbon oxidation is catalyzed by members of the cytochrome P-450 family of oxidases. This paper examines the impact that various structural features of 1,4-disubstituted-1,2,3,6-tetrahydropyridinyl derivatives have on the oxidative fate of this class of compound.