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

Parkinson'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.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2000

Author dc:creator

• Isin, Emre M.

Chair dc:contributor.committeechair

• Castagnoli, Neal Jr.

Committee members dc:contributor.committeemember

• Kingston, David G. I.
• Tanko, James M.
• Dorn, Harry C.

• indazole
• neuroprotection
• organic reaction mechanisms
• SAR
• tetrahydropyridinyl-based prodrugs

Statement dc:rights

• In Copyright

Licence dc:rights.uri

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

Dc Identifier Other

etd-11272000-120319

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/35829