Studies on the Monoamine Oxidase-B-Catalyzed Biotransformation of 4-Azaaryl-1-methyl-1,2,3,6-tetrahydropyridine Derivatives

The substrate properties of a series of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinyl (MPTP) analogues in which the C-4 phenyl group has been replaced with various 4-azaaryl moieties have been examined in an effort to evaluate the contribution of electronic, polar, and steric parameters to the MAO-B-catalyzed oxidation of this type of cyclic tertiary allylamine to the corresponding dihydropyridinium metabolite. No significant correlation could be found with the calculated energy of the C−H bond undergoing cleavage. A general trend, however, was observed between the magnitude of the log P value with the magnitude of k cat/K m. The results indicate that the placement of a polar nitrogen atom in the space occupied by the phenyl group of MPTP leads to a dramatic decrease in substrate properties. Enhanced substrate properties, however, were observed when benzoazaarenes replaced the corresponding five-membered azaarenes. These results are consistent with our previously published molecular model of the active site of MAO-B.