CHEMICAL-MODEL STUDIES ON THE MONOAMINE OXIDASE-B CATALYZED OXIDATIONOF 4-SUBSTITUTED 1-CYCLOPROPYL-1,2,3,6-TETRAHYDROPYRIDINES

Two catalytic pathways have been proposed for the flavoenzyme monoamin e oxidase B (MAO-B)-one based on an initial single electron transfer ( SET) step from the nitrogen lone pair and the second based on an initi al alpha-carbon hydrogen atom transfer (HAT) step. The SET pathway is consistent with the mechanism based inactivation properties of various cyclopropylamines. The observation that MAO-B catalyzes the efficient oxidation of certain lopropyl-4-substituted-1,2,3,6-tetrahydropyridin es to the corresponding dihydropyridinium metabolites suggests that th e catalytic pathway for these cyclic tertiary allylamines may not proc eed via the putative SET generated aminyl radical cations. The present paper describes the chemical fate of a series of N-cyclopropyltetrahy dropyridines examined under reaction conditions that model the SET and the HAT pathways. All of the test compounds were rapidly converted un der HAT reaction conditions to their dihydropyridinium products. Altho ugh the test compounds also were oxidized rapidly under SET conditions , no evidence for dihydropyridinium product formation was observed. Th e products that were identified most likely were formed after cyclopro pyl ring opening of the initially formed cyclopropylaminyl radical cat ion. The results are discussed in terms of the mechanism of MAO-B cata lysis. (C) 1998 Published by Elsevier Science Ltd. All rights reserved .