title: Synthesis and monoamine oxidase B catalyzed oxidation of C-4 heteroaromatic substituted 1,2,3,6-tetrahydropyridine derivatives.
abstract: The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron transfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selected N-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives have led us to consider a mechanism for these cyclic tertiary allylamines which may not necessarily involve the aminyl radical cation as required by an initial single-electron transfer step. The studies summarized in this paper were undertaken to explore further the structural features that determine the MAO-B substrate and/or inactivator properties of various 1,4-disubstituted tetrahydropyridine derivatives. We report here the results of our studies on the synthesis and MAO-B catalyzed oxidation of 1-methyl- and 1-cyclopropyl-1,2,3,6-tetrahydropyridine derivatives bearing a variety of heteroaromatic groups at C-4. All of the N-cyclopropyltetrahydropyridine analogs were time and concentration dependent inhibitors of MAO-B while all of the N-methyltetrahydropyridine analogs and the N-cyclopropyl-4-(1-methyl-2-pyrryl)tetrahydropyridine analog were substrates. The substrate properties (Kcat/KM) covered a range of 6 to 1800 min-1 mM-1 while the range for the inactivator properties for which Kinact/KI values could be obtained was 0.1-1.0 min-1 mM-1. The partition ratios for the N-cyclopropyl analogs varied from 4 to 17 except for the 4-(1-methyl-2-pyrryl) analog, which had a partition ratio of 400. These results are discussed in terms of the putative allylic radical intermediate and in the context of the hydrogen atom transfer and single-electron transfer based mechanisms.
authors.affiliation: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061-0212, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Nimkar
authors.forename: A H
authors.initials: AH
authors.lastname: Anderson
authors.forename: J M
authors.initials: JM
authors.lastname: Rimoldi
authors.forename: M
authors.initials: M
authors.lastname: Stanton
authors.forename: K P
authors.initials: KP
authors.lastname: Castagnoli
authors.forename: S
authors.initials: S
authors.lastname: Mabic
authors.forename: Y X
authors.initials: YX
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Castagnoli
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D000818:Animals; D002384:Catalysis; D002417:Cattle; D007700:Kinetics; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011725:Pyridines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase