Synthetic and metabolic studies on 1-methyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine, a neurotoxic analog of the Parkinsonian inducing agent MPTP

dc.contributor.authorBai, Hongen
dc.contributor.committeechairCastagnoli, Neal Jr.en
dc.contributor.committeememberMerola, Joseph S.en
dc.contributor.committeememberBecker, David A.en
dc.contributor.departmentChemistryen
dc.date.accessioned2014-03-14T21:42:08Zen
dc.date.adate2009-08-04en
dc.date.available2014-03-14T21:42:08Zen
dc.date.issued1991-12-02en
dc.date.rdate2009-08-04en
dc.date.sdate2009-08-04en
dc.description.abstract1-Methyl-4-(1-methylpyrrol-2-yl)-1 ,2,3,6-tetrahydropyridine (TMMP) is a neurotoxic analog of the parkinsonian inducing agent MPTP. TMMP and its putative metabolites 1-methyl-4-(1-methylpyrrol-2-yl)-2,3-dihydropyridinium (MMDP+) and 1-methyl-4-(1-methylpyrrol-2-yl)pyridinium (MMP+) were synthesized and fully characterized. Substrate/inactivation properties of TMMP and its analog N-propargyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine with MAO-B were investigated. Kinetic data was obtained, including Km and Vmax for TMMP as an MAO-B substrate, and KI and kinact values for N-propargyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine. The metabolic studies of TMMP and MMDP+ were conducted with an HPLC diode array assay. Both in-vivo and in-vitro metabolic studies showed that TMMP is oxidized to its dihydropyridinium species (MMDP+) in a reaction catalyzed by MAO-B. MMDP+ undergoes autoxidation to form the pyridinium species (MMP+), the mechanism of this conversion is not clear. In-vitro studies show that MAO-B is not responsible for this conversion and the oxidation of MMDP+ to MMP+ is likely to be enzyme catalyzed. Toxicity investigations include dopamine depletion studies of TMMP and MMDP+, mitochondrial respiration and microdialysis studies of MMDP+ and MMP+. The above studies show that TMMP is an MPTP-type neurotoxin.en
dc.description.degreeMaster of Scienceen
dc.format.extent123 leavesen
dc.format.mediumBTDen
dc.format.mimetypeapplication/pdfen
dc.identifier.otheretd-08042009-040225en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-08042009-040225/en
dc.identifier.urihttp://hdl.handle.net/10919/44138en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartLD5655.V855_1991.B34.pdfen
dc.relation.isformatofOCLC# 25490710en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject.lccLD5655.V855 1991.B34en
dc.subject.lcshMethylphenyltetrahydropyridineen
dc.subject.lcshParkinson's diseaseen
dc.titleSynthetic and metabolic studies on 1-methyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine, a neurotoxic analog of the Parkinsonian inducing agent MPTPen
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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