This dissertation is concerned with the metabolic bioactivation of several amines which are either known or suspected to be neurotoxic and with the exploration of bioactivation processes in order to generate metabolites with therapeutic potential. The following three programs were pursued in this work:
(1) Theoretical considerations and recent experimental data have prompted an investigation of the neurotoxicological properties of the 6-hydroxydopamine analog 2-methylamino-1-(2,4,5-trihydroxyphenyl) propane and its possible precursor intermediate 1-(2-hydroxy-4,5-methylenedioxyphenyl)-2-methylaminopropane, potential metabolites of the serotonergic neurotoxin 2-methylamino- 1-(4,5-methylenedioxyphenyl)propane, (Methylenedioxymethamphetamine, MDMA). The syntheses and serotonergic neurotoxic properties of the potential metabolites are discussed.
(2) The further biotransformation of the 1-(1-phenylcyclohexy!)- 3,4,5,6-tetrahydropyridinium metabolite derived from_ the psychosis inducing agent phencyclidine [1-(1-phenylcyclohexy]l)- piperidine, PCP] has been examined in rat liver and brain subcellular fractions. In the presence of brain mitochondria this tetrahydropyridinium compound was converted to 1-(phenylcyclohexyl)- 1,2,3,4-tetrahydropyridine-5-carboxaldehyde. The same product was identified in the corresponding liver mitochondrial and microsomal incubation mixtures and in liver microsomal incubations of phencyclidine. The chemical conversion of the synthetic tetra hydropyridinium perchlorate to this product by N⁵-formyltetrahydrofolic acid (folinic acid) suggests that the metabolic reaction is mediated by a transformylation process involving this or the corresponding N¹⁰-formyltetrahydrofolic acid.
(3) Extensive substrate-activity studies have established that only those 1,2,3,6-tetrahydropyridine derivatives bearing a lipophilic C-4 substituent and an N-methyl group are likely to be good monoamine oxidase B substrates. The design and synthesis of potential prodrugs based on this enzyme-substrate selectivity has been pursued with model compounds. / Ph. D.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/38916 |
| Date | 28 July 2008 |
| Creators | Zhao, Zhiyang |
| Contributors | Chemistry, Castagnoli, Neal Jr., Bell, Harold M., Gibson, Harry W., Long, Gary L., Merola, Joseph S. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation, Text |
| Format | xv, 208 leaves, BTD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | OCLC# 25146118, LD5655.V856_1991.Z426.pdf |
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