{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/30611"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/30611","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"The Investigation of the Active Sites of Monoamine Oxidase (MAO) A and B and the Study of MAO-A Mediated Neurotoxicity Using 4-Substituted Tetrahydropyridines","abstract":"The mitochondrial membrane bound flavoenzymes monoamine oxidase A and B (MAO-A and MAO-B) catalyze the a-carbon oxidation of a variety of amines including neurotransmitters such as dopamine and serotonin. Although the primary structures of these enzymes have been established from the corresponding gene sequences, relatively little is known regarding the structural features of the active sites which lead to the selectivities observed with various substrates and inhibitors. In spite of many efforts, these enzymes have not been crystallized. In the absence of X-ray structures, the design, synthesis, and evaluation of biological activity remain the only way to assess a view of the active sites, through SAR and QSAR studies. The excellent MAO-A and/or B substrate and inhibitor properties of various 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives offer an interesting opportunity to probe the active sites of MAO-A and MAO-B. In an effort to explore the spatial features of the active sites, we have synthesized series of substituted tetrahydropyridines, evaluated their biological activity with purified MAO-A and MAO-B, and carried out a topological analysis of the MAO active sites using molecular modeling. In addition, the results described in this thesis provide evidence that the MAO-A and MAO-B active sites differ in shape, regions of activity, and areas that tolerate polar interactions. The role of MAO in neurodegenerative processes such as Parkinson's Disease has been recognized for some time. The structurally unique parkinsonian inducing substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated to neurotoxic metabolites. The mechanism of neurotoxicity has been studied extensively and it is known that MAO-B catalyzes the conversion of MPTP to the 2,3-dihydro-1-methyl-4-phenylpyridinium species (MPDP+) which undergoes further oxidation to the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MPP+). However, the role of MAO-A in mediating a neurotoxic response, has not been fully defined due to the lack of selective MAO-A substrates. In this thesis, we have investigated the neurotoxic potential of several tetrahydropyridines in C57Bl/6 mice and the ability of selective inhibitors to protect against the expression of MAO mediated neurotoxicity.","abstract_html":"The mitochondrial membrane bound flavoenzymes monoamine oxidase A and B (MAO-A and MAO-B) catalyze the a-carbon oxidation of a variety of amines including neurotransmitters such as dopamine and serotonin. Although the primary structures of these enzymes have been established from the corresponding gene sequences, relatively little is known regarding the structural features of the active sites which lead to the selectivities observed with various substrates and inhibitors. In spite of many efforts, these enzymes have not been crystallized. In the absence of X-ray structures, the design, synthesis, and evaluation of biological activity remain the only way to assess a view of the active sites, through SAR and QSAR studies. The excellent MAO-A and/or B substrate and inhibitor properties of various 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives offer an interesting opportunity to probe the active sites of MAO-A and MAO-B. In an effort to explore the spatial features of the active sites, we have synthesized series of substituted tetrahydropyridines, evaluated their biological activity with purified MAO-A and MAO-B, and carried out a topological analysis of the MAO active sites using molecular modeling. In addition, the results described in this thesis provide evidence that the MAO-A and MAO-B active sites differ in shape, regions of activity, and areas that tolerate polar interactions. The role of MAO in neurodegenerative processes such as Parkinson's Disease has been recognized for some time. The structurally unique parkinsonian inducing substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated to neurotoxic metabolites. The mechanism of neurotoxicity has been studied extensively and it is known that MAO-B catalyzes the conversion of MPTP to the 2,3-dihydro-1-methyl-4-phenylpyridinium species (MPDP+) which undergoes further oxidation to the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MPP+). However, the role of MAO-A in mediating a neurotoxic response, has not been fully defined due to the lack of selective MAO-A substrates. In this thesis, we have investigated the neurotoxic potential of several tetrahydropyridines in C57Bl/6 mice and the ability of selective inhibitors to protect against the expression of MAO mediated neurotoxicity.","abstract_has_math":false,"creators":["Palmer, Sonya Lenette"],"institution":"Virginia Tech","degree_name":"Ph. D.","degree_level":"doctoral","degree_discipline":"Chemistry","degree_department":"Chemistry","school":null,"contributors":[],"advisors":[],"committee_chairs":["Castagnoli, Neal Jr."],"committee_members":["Bell, Harold M.","Kingston, David G. I.","Tanko, James M.","Wolfe, James F.","Taylor, Larry T.","Kazakevich, Yuri V."],"year":1998,"date_issued":"1998-05-18","date_published":"1998-05-18","updated_at":"2026-07-22T22:19:37Z","subjects":["Monoamine Oxidase","Active Sites","Neurotoxicity","Enzymology"],"languages":[],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-5698-103410"],"render_values":[{"text":"etd-5698-103410","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/10919/30611","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Castagnoli, Neal Jr."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Bell, Harold M.","Kingston, David G. 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Although the primary structures of these enzymes have been established from the corresponding gene sequences, relatively little is known regarding the structural features of the active sites which lead to the selectivities observed with various substrates and inhibitors. In spite of many efforts, these enzymes have not been crystallized. In the absence of X-ray structures, the design, synthesis, and evaluation of biological activity remain the only way to assess a view of the active sites, through SAR and QSAR studies. The excellent MAO-A and/or B substrate and inhibitor properties of various 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives offer an interesting opportunity to probe the active sites of MAO-A and MAO-B. In an effort to explore the spatial features of the active sites, we have synthesized series of substituted tetrahydropyridines, evaluated their biological activity with purified MAO-A and MAO-B, and carried out a topological analysis of the MAO active sites using molecular modeling. In addition, the results described in this thesis provide evidence that the MAO-A and MAO-B active sites differ in shape, regions of activity, and areas that tolerate polar interactions. The role of MAO in neurodegenerative processes such as Parkinson's Disease has been recognized for some time. The structurally unique parkinsonian inducing substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated to neurotoxic metabolites. The mechanism of neurotoxicity has been studied extensively and it is known that MAO-B catalyzes the conversion of MPTP to the 2,3-dihydro-1-methyl-4-phenylpyridinium species (MPDP+) which undergoes further oxidation to the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MPP+). However, the role of MAO-A in mediating a neurotoxic response, has not been fully defined due to the lack of selective MAO-A substrates. In this thesis, we have investigated the neurotoxic potential of several tetrahydropyridines in C57Bl/6 mice and the ability of selective inhibitors to protect against the expression of MAO mediated neurotoxicity."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph. D."]},{"key":"dc:title","label":"Title","values":["The Investigation of the Active Sites of Monoamine Oxidase (MAO) A and B and the Study of MAO-A Mediated Neurotoxicity Using 4-Substituted Tetrahydropyridines"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Castagnoli, Neal Jr."],"dc:contributor.committeemember":["Bell, Harold M.","Kingston, David G. I.","Tanko, James M.","Wolfe, James F.","Taylor, Larry T.","Kazakevich, Yuri V."],"dc:contributor.department":["Chemistry"],"dc:creator":["Palmer, Sonya Lenette"],"dc:date.accessioned":["2014-03-14T20:22:13Z"],"dc:date.available":["2014-03-14T20:22:13Z","1999-06-12"],"dc:date.issued":["1998-05-18"],"dc:description.abstract":["The mitochondrial membrane bound flavoenzymes monoamine oxidase A and B (MAO-A and MAO-B) catalyze the a-carbon oxidation of a variety of amines including neurotransmitters such as dopamine and serotonin. Although the primary structures of these enzymes have been established from the corresponding gene sequences, relatively little is known regarding the structural features of the active sites which lead to the selectivities observed with various substrates and inhibitors. In spite of many efforts, these enzymes have not been crystallized. In the absence of X-ray structures, the design, synthesis, and evaluation of biological activity remain the only way to assess a view of the active sites, through SAR and QSAR studies. The excellent MAO-A and/or B substrate and inhibitor properties of various 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives offer an interesting opportunity to probe the active sites of MAO-A and MAO-B. In an effort to explore the spatial features of the active sites, we have synthesized series of substituted tetrahydropyridines, evaluated their biological activity with purified MAO-A and MAO-B, and carried out a topological analysis of the MAO active sites using molecular modeling. In addition, the results described in this thesis provide evidence that the MAO-A and MAO-B active sites differ in shape, regions of activity, and areas that tolerate polar interactions. The role of MAO in neurodegenerative processes such as Parkinson's Disease has been recognized for some time. The structurally unique parkinsonian inducing substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated to neurotoxic metabolites. The mechanism of neurotoxicity has been studied extensively and it is known that MAO-B catalyzes the conversion of MPTP to the 2,3-dihydro-1-methyl-4-phenylpyridinium species (MPDP+) which undergoes further oxidation to the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MPP+). However, the role of MAO-A in mediating a neurotoxic response, has not been fully defined due to the lack of selective MAO-A substrates. In this thesis, we have investigated the neurotoxic potential of several tetrahydropyridines in C57Bl/6 mice and the ability of selective inhibitors to protect against the expression of MAO mediated neurotoxicity."],"dc:description.degree":["Ph. D."],"dc:identifier.other":["etd-5698-103410"],"dc:identifier.uri":["http://hdl.handle.net/10919/30611"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["Monoamine Oxidase","Active Sites","Neurotoxicity","Enzymology"],"dc:title":["The Investigation of the Active Sites of Monoamine Oxidase (MAO) A and B and the Study of MAO-A Mediated Neurotoxicity Using 4-Substituted Tetrahydropyridines"],"dc:type":["Dissertation"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Ph. D."],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:19:37Z"}