Potential Prodrugs of the Neuronal Nitric Oxide Synthase and Monoamine Oxidase Inhibitor 7-Nitroindazole and Structurally Related Compounds

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dc.contributor.authorIsin, Emre M.en
dc.contributor.committeechairCastagnoli, Neal Jr.en
dc.contributor.committeememberKingston, David G. I.en
dc.contributor.committeememberTanko, James M.en
dc.contributor.committeememberDorn, Harry C.en
dc.contributor.departmentChemistryen
dc.date.accessioned2014-03-14T20:48:23Zen
dc.date.adate2000-12-06en
dc.date.available2014-03-14T20:48:23Zen
dc.date.issued2000-10-30en
dc.date.rdate2001-12-06en
dc.date.sdate2000-11-27en
dc.description.abstractParkinson's disease (PD) is a progressive neurodegenerative disorder of unknown cause that afflicts about 1.5 million Americans. The characteristic feature of PD is a deficiency of dopamine in the terminals of nigrostriatal neurons. Two enzyme systems, the neuronal form of nitric oxide synthase (nNOS) and monoamine oxidase B (MAO-B), have been linked to neurodegenerative pathways leading to PD. Several MAO-B and nNOS inhibitors have been evaluated for their neuroprotective properties in the mouse model of neurodegeneration which employs the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). One such compound is 7-nitroindazole (7-NI), a compound which is reported to inhibit both enzymes. This thesis focuses on the synthesis and biological evaluation of a potential prodrug form of 7-NI and related indazolyl containing compounds which are designed to release the active drugs following a metabolic bioactivation process. These studies have led to a detailed description of the nucleophilic aromatic substitution reactions between 4-chloro-1-methylpyridinium iodide and the indazolyl reactants that were employed as the initial step in the synthesis of the target compounds. The MAO-B substrate and inhibition properties of these "prodrugs" as well as the parent indazolyl compounds were examined. The results are discussed in relation to a previously developed active site model of MAO-B.en
dc.description.degreeMaster of Scienceen
dc.identifier.otheretd-11272000-120319en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-11272000-120319/en
dc.identifier.urihttp://hdl.handle.net/10919/35829en
dc.publisherVirginia Techen
dc.relation.haspartChapter4.pdfen
dc.relation.haspartChapter5-7.pdfen
dc.relation.haspartChapter1-3.pdfen
dc.relation.haspart1Main.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectindazoleen
dc.subjectneuroprotectionen
dc.subjectorganic reaction mechanismsen
dc.subjectSARen
dc.subjecttetrahydropyridinyl-based prodrugsen
dc.titlePotential Prodrugs of the Neuronal Nitric Oxide Synthase and Monoamine Oxidase Inhibitor 7-Nitroindazole and Structurally Related Compoundsen
dc.typeThesisen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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