Scholarly
    Communications Project


Document Type:Dissertation
Name:Andrea H. Anderson
Email address:anon795@vt.edu
URN:
Title:Mechanistic Studies on the Monoamine Oxidase B Catalyzed Oxidation of 1,4-Disubstituted Tetrahydropyridine Derivatives
Degree:Doctor of Philosophy
Department:Chemistry
Committee Chair: Neal Castagnoli, Jr.
Chair's email:ncastagnoli@chemserver.chem.vt.edu
Committee Members:
Keywords:monoamine oxidase, single electron transfer, hydrogen atom transfer
Date of defense:June 10, 1997
Availability:Release the entire work for Virginia Tech access only.
After one year release worldwide only with written permission of the student and the advisory committee chair.

Abstract:

The flavin-containing monoamine oxidases (MAO) A and B catalyze the oxidative deamination of primary and secondary amines. The overall process involves a two electron oxidation of the amine to the iminium with concomitant reduction of the flavin. Based on extensive studies with a variety of chemical probes, Silverman and colleagues have proposed a catalytic pathway for the processing of amine substrates and inactivators by MAO-B that is initiated by a single electron transfer (SET) step from the nitrogen lone pair to the oxidized flavin followed by a-proton loss from the resulting amine radical cation that leads to a carbon radical. Subsequent transfer of the second electron leads to the reduced flavin and the iminium product. In the case of N-cyclopropylamines, the initially formed amine radical cation is proposed to undergo rapid ring opening to form a highly reactive primary carbon centered radical that is thought to be responsible for inactivation of the enzyme. In this thesis we have exploited the unique substrate and inactivator properties of 1,4-disubstituted tetrahydropyridine derivatives to probe the mechanism of MAO-B catalysis. Reports of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a structurally unique substrate of MAO-B initiated these studies. Consistent with the SET pathway, the N-cyclopropyl analog of MPTP proved to be an efficient time and concentration dependent inactivator but not a substrate of MAO-B. On the other hand, the 4-benzyl-1- cyclopropyl analog is both a substrate and inactivator of MAO-B. These properties may not be consistent with the  obligatory formation of a cyclopropylaminyl radical cation intermediate. In an attempt to gain further insight into the mechanism associated with the MAO catalyzed oxidation of 1,4-disubstituted tetrahydropyridines, deuterium isotope effects studies on both the substrate and inactivation properties of the 4-benzyl-1- cyclopropyl derivative were undertaken. A series of 1-methyl- and 1-cyclopropyltetrahydropyridine derivatives bearing various heteroaro-matic groups at C-4 also have been examined. The MAO-B substrate properties, inactivator properties and partition ratios for these compounds together with  preliminary results from chemical model studies are discussed in terms of the MAO-B catalytic pathway. 

List of Attached Files

Chapter_2.pdf Chapter_3.pdf Chapter_4-8.pdf
Title_page.pdf chapter__201.pdf

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