{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/44532"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/44532","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Studies on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and analogs","abstract":"The 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.","abstract_html":"The 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.","abstract_has_math":false,"creators":["Bucy, Teresa B."],"institution":"Virginia Tech","degree_name":"Master of Science","degree_level":"masters","degree_discipline":"Chemistry","degree_department":"Chemistry","school":null,"contributors":[],"advisors":[],"committee_chairs":["Castagnoli, Neal Jr."],"committee_members":["Merola, Joseph S.","Kingston, David G. I."],"year":1991,"date_issued":"1991-02-07","date_published":"1991-02-07","updated_at":"2026-07-22T22:19:45Z","subjects":[],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-09052009-040222"],"render_values":[{"text":"etd-09052009-040222","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/10919/44532","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Castagnoli, Neal Jr."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Merola, Joseph S.","Kingston, David G. 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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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Master of Science"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["BTD"]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Studies on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and analogs"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Castagnoli, Neal Jr."],"dc:contributor.committeemember":["Merola, Joseph S.","Kingston, David G. I."],"dc:contributor.department":["Chemistry"],"dc:creator":["Bucy, Teresa B."],"dc:date.accessioned":["2014-03-14T21:44:25Z"],"dc:date.available":["2014-03-14T21:44:25Z","2009-09-05"],"dc:date.issued":["1991-02-07"],"dc:description.abstract":["The 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."],"dc:description.degree":["Master of Science"],"dc:format.medium":["BTD"],"dc:format.mimetype":["application/pdf"],"dc:identifier.other":["etd-09052009-040222"],"dc:identifier.uri":["http://hdl.handle.net/10919/44532"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:title":["Studies on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and analogs"],"dc:type":["Thesis"],"dc:type.dcmitype":["Text"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["masters"],"thesis:degree_name":["Master of Science"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:19:45Z"}