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Studies on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and analogs

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dc.contributor.authorBucy, Teresa B.en
dc.contributor.committeechairCastagnoli, Neal Jr.en
dc.contributor.committeememberMerola, Joseph S.en
dc.contributor.committeememberKingston, David G. I.en
dc.contributor.departmentChemistryen
dc.date.accessioned2014-03-14T21:44:25Zen
dc.date.adate2009-09-05en
dc.date.available2014-03-14T21:44:25Zen
dc.date.issued1991-02-07en
dc.date.rdate2009-09-05en
dc.date.sdate2009-09-05en
dc.description.abstractThe cyclic allylamine I-methyl-4-phenyl-l ,2,3,6-tetrahydropyridine (MPTP) is a potent and specific neurotoxin that causes a parkinsonian like syndrome in humans and subhuman primates. Research has revealed that MPTP is bioactivated in a reaction catalyzed by flavin containing monoamine oxidase B (MAO B) to yield the dihydropyridinium species MPDP+ which undergoes further oxidation to the ultimate toxin, the I-methyl-4-phenylpyridinium species MPP+. The research summarized in this thesis describes a potential model reaction for the MAO catalyzed conversion of MPTP to MPDP+ and the synthesis and biological evaluation of MPTP analogs bearing a heteroatom at C-4 of the tetrahydropyridine ring. The model for the enzyme catalyzed oxidation of MPTP to MPDP+ is based on the anhydride mediated conversion of MPTP Noxide to MPDP+. This reaction pathway was visualized to mimic a reaction sequence in which an FAD-MPTP adduct cleaves to yield MPDP+ and FADH2. Attempts were made to assess the isotope effect associated with this reaction and to compare that value with the corresponding values for the MAO-B catalyzed reaction [D(V max/Km) = 7-9], the cytochrome P-450 catalyzed reaction [D(V max/Km) = 1.04] and the electrochemical oxidation (D k = 1.35). Unfortunately experimental difficulties prevented a complete analysis of the problem. Specialized equipment will be required to obtain accurate isotope effect measurements. The second study concerns the preparation of the MPTP analogs 4-chloro-, 4-cyano-, and 4-( 4-fluorophenoxy)-1,2,3,6-tetrahydropyridine as potential MAO B substrates that could generate neurotoxic pyridinium metabolites. Results obtained with MAO B have revealed that the dihydropyridinium intermediate formed from 4-( 4-fluorophenoxy)-1 ,2,3, 6-tetrahydropyridine undergoes spontaneous hydrolysis to generate 4-fluorophenol and 1- methyl-4-pyridone. The significance of this finding with respect to neurotoxic mechanisms and design are discussed.en
dc.description.degreeMaster of Scienceen
dc.format.extentxv, 185 leavesen
dc.format.mediumBTDen
dc.format.mimetypeapplication/pdfen
dc.identifier.otheretd-09052009-040222en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-09052009-040222/en
dc.identifier.urihttp://hdl.handle.net/10919/44532en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartLD5655.V855_1991.B937.pdfen
dc.relation.isformatofOCLC# 23812459en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject.lccLD5655.V855 1991.B937en
dc.subject.lcshMethylphenyltetrahydropyridine -- Researchen
dc.titleStudies on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and analogsen
dc.typeThesisen
dc.type.dcmitypeTexten
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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