MECHANISTIC STUDIES ON THE MONOAMINE-OXIDASE-B CATALYZED OXIDATION OF1,4-DISUBSTITUTED TETRAHYDROPYRIDINES

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