PROBING THE MECHANISM OF BIOACTIVATION OF MPTP TYPE ANALOGS BY MONOAMINE-OXIDASE B - STRUCTURE-ACTIVITY STUDIES ON SUBSTITUTED PHENOXY-1-CYCLOPROPYL-1,2,3,6-TETRAHYDROPYRIDINES, -PHENYL-1-CYCLOPROPYL-1,2,3,6-TETRAHYDROPYRIDINES, AND OPHENOXY-1-CYCLOPROPYL-1,2,3,6-TETRAHYDROPYRIDINES

Previous studies have shown that 4-benzyl-1-cyclopropyl-1,2,3,6-tetrah ydropyridine is an excellent monoamine oxidase B (MAO-B) substrate (k( cat)/K-M = 1538 min(-1) mM(-1)) although the corresponding 4-phenyl an alog displays MAO-B inactivating properties only. This behavior led us to speculate that the pathway for the MAO-B catalyzed oxidation of th ese tetrahydropyridines may not necessarily proceed via an initial sin gle electron transfer step as proposed by others but rather through an initial alpha-carbon hydrogen atom abstraction step. In the present s tudies we have examined the interactions of various 4-phenoxy-, 4-phen yl-, and iophenoxy-1-cyclopropyl-1,2,3,6-tetrahydropyridine derivative s, some of which bear substituents on the phenyl ring. The 4-thiopheno xy- and all of the 4-phenoxytetrahydropyridine derivatives proved to b e substrates but not inactivators of MAO-B, while several of the 4-phe nyltetrahydropyridine derivatives were inactivators but not substrates . A case of particular interest was pyl-4-(2-methylphenyl)-1,2,3,6-tet rahydropyridine, which displayed only substrate properties. The result s are discussed in terms of two catalytic pathways, one of which invol ves partitioning of the proposed cyclopropylaminyl radical cation inte rmediate between cyclopropyl ring opening and proton loss while the se cond involves partitioning of the parent amine between an initial sing le electron transfer step, leading to cyclopropylaminyl radical cation formation and enzyme inactivation, and an initial alpha-carbon hydrog en atom abstraction step, leading to an allylic radical and dihydropyr idinium product formation.