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. / Master of Science
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/44532 |
| Date | 05 September 2009 |
| Creators | Bucy, Teresa B. |
| Contributors | Chemistry, Castagnoli, Neal Jr., Merola, Joseph S., Kingston, David G. I. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis, Text |
| Format | xv, 185 leaves, BTD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | OCLC# 23812459, LD5655.V855_1991.B937.pdf |
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