Mechanistic studies on the monoamine oxidase B catalyzed oxidation of 1,4-disubstituted tetrahydropyridines.

Previous studies have established that 1-cyclopropyl-4-phenyl-1,2,3,6- tetrahydropyridine (6) is an efficient time and concentration dependent inhibitor of the flavin containing enzyme monoamine oxidase B (MAO-B). This behavior is consistent with a proposed mechanism based inactivation pathway initiated by transfer of one of the nitrogen nonbonding pairs of electrons to the oxidized flavin cofactor to generate an amine radical cation intermediate. Subsequent opening of the strained cyclopropylamine ring is thought to lead to a primary carbon centered radical that inactivates the enzyme by covalent modification of the flavin or an essential active site functionality. We now have examined the MAO-B inactivator and substrate properties of 4-benzyl-1-cyclopropyl-1,2,3,6-tetrahydropyridine (11). This compound also is a time and concentration dependent inhibitor of MAO-B. Unexpectedly, however, compound 11 proved to be an excellent MAO-B substrate. These results are discussed in terms of possible catalytic pathways for the MAO-B catalyzed oxidation of 1,4-disubstituted-1,2,3,6- tetrahydropyridines.