Studies on the monoamine oxidase substrate/inactivator properties of piperidine analogs of the neurotoxin MPTP

Abstract

The unexpected monoamine oxidase (MAO) substrate properties of 1-cyclopropyl-4-substituted-1 ,2,3,6-tetrahydropyridines have been interpreted in terms of partitioning of these tertiary cyclic allylamines between substrate turnover and ring opening inactivation processes. To evaluate further this proposal, we examined the bioactivities of the related saturated analogs. Several 1,4-disubstituted piperidine derivatives were synthesized and their interactions with MAO-A and MAO-B were characterized. These compounds displayed poor substrate properties toward MAO-A and MAO-B and led to the expected α-carbon oxidized metabolites which were fully characterized.

Both the N-methyl and N-cyclopropyl derivatives were good inactivators of MAO-B, suggesting that some species other than the radical resulting from cyclopropyl ring opening is responsible for the inactivation. Both the N-methyl and N-cyclopropyl derivatives also inactivated MAO-A. In this instance, the N-cyclopropyl analogs were much more potent inactivators than the N-methyl analogs. These results suggest that the radical derived from cyclopropyl ring opening may be involved in this inactivation process.

The MAO substrate/inactivator properties of these piperidine analogs are discussed in terms of current proposed mechanisms for the MAO catalyzed oxidation of amines.