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 understood. This situation has improved somewhat with structure-activity studies that have been performed on nuclear-substituted pargyline derivatives and 4-substituted 1-methyl-1,2,3,6-tetrahydropyridine derivatives. 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-substrate activity analysis with the aid of a series of 4-phenoxytetrahydropyridine 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. The best defined structural parameter relating to selectivity again was the relatively better MAO-A substrate properties of tetrahydropyridine derivatives bearing bulky C-4 substituents. Attempts to identify stereoelectronic effects related to substrate properties and selectivity with this series of compounds were not successful. Although some structural correlates with substrate activity can be made, overall the present state of knowledge is inadequate to provide good descriptors of structural features that characterize MAO-A and MAO-B substrates.
Wang
Y X
YX
Department of Chemistry, Virginia Polytechnic Institute, Blacksburg 24061-0212, USA.
Castagnoli
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D002417:Cattle; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D010084:Oxidation-Reduction; D010920:Placenta / Q000201:enzymology; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D007527:Isoenzymes; D011725:Pyridines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase