STUDIES ON THE MONOAMINE-OXIDASE (MAO)-CATALYZED OXIDATION OF PHENYL-SUBSTITUTED 1-METHYL-4-PHENOXY-1,2,3,6-TETRAHYDROPYRIDINE DERIVATIVES - FACTORS CONTRIBUTING TO MAO-A AND MAO-B SELECTIVITY

The structural parameters responsible for the substrate and inhibitor selectivities of the monoamine oxidases (MAO) A and B remain poorly un derstood. This situation has improved somewhat with structure-activity studies that have been performed on nuclear-substituted pargyline der ivatives and 4-substituted 1-methyl-1,2,3,6-tetrahydropyridine derivat ives. The results of these studies suggest that the active site of MAO -A is sterically more accommodating than the active site of MAO-B. In the present work we have undertaken a more systematic structure-substr ate activity analysis with the aid of a series of 4-phenoxytetrahydrop yridine analogs substituted at the para, meta, and ortho positions of the phenyl ring with chloro, methoxy, methyl, nitro, and phenyl groups . All of the compounds proved to be good substrates for both MAO-A and MAO-B, and all were better MAO-A substrates than MAO-B substrates. Th e best defined structural parameter relating to selectivity again was the relative:ly better MAO-A substrate properties of tetrahydropyridin e derivatives bearing bulky C-4 substituents. Attempts to identify ste reoelectronic effects related to substrate properties and selectivity with this series of compounds were not successful. Although some struc tural correlates with substrate activity can be made, overall the pres ent state of knowledge is inadequate to provide good descriptors of st ructural features that characterize MAO-A and MAO-B substrates.