Synthetic and metabolic studies on centrally acting amines

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.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

1991

Author dc:creator

• Zhao, Zhiyang

Chair dc:contributor.committeechair

• Castagnoli, Neal Jr.

Committee members dc:contributor.committeemember

• Bell, Harold M.
• Gibson, Harry W.
• Long, Gary L.
• Merola, Joseph S.

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

etd-07282008-134847

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/38916