{"id":{"repo_id":"montana-tech","oai_identifier":"oai:scholarworks.umt.edu:etd-1116"},"canonical_url":"https://search.dev.ndltd.org/etd/montana-tech/oai:scholarworks.umt.edu:etd-1116","repository":{"repo_id":"montana-tech","name":"Montana Technology","base_url":"https://scholarworks.umt.edu/do/oai/"},"display":{"title":"BIOISOSTERES OF AMPA: CONFORMATIONAL ANALYSIS AND STRUCTURE ACTIVITY RELATIONSHIP","abstract":"Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Concentrations of L-glutamate in the CNS are regulated by a family of excitatory amino acid transporters (EAATs) that rapidly sequester and concentrate glutamate in glia and neurons, and thereby influence transmitter access to EAA receptors. In contrast to the EAAT-mediated uptake of L-Glu, the system Xc- (SXc-) transporter (an obligate exchanger of L-glutamate and L-cystine) has been implicated in the export of L-Glu from CNS cells in such a manner that it can access and activate EAA receptors. The significance of SXc- actions is reflected in the range of CNS processes including: drug addiction, brain tumor growth and oxidative protection. Recent work has focused on the synthesis of analogs and bioisosteres of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), including lipophilic analogs using lateral metalation and electrophilic quenching and their evaluations at the system xc- transporter. Bioisosteres which are not limited to amino acids were synthesized from a common intermediate. During the synthesis of hydrazone bioisosteres, most electron rich hydrazines undergo ring closer to form fused bicyclic systems, the isoxazolo[3,4-d]pyridazinones. Several hydrazone acids synthesized, bind to the SXc- with affinities comparable to those of the endogenous substrates. In contrast, the isoxazolo [3,4-d]pyridazinone analogs exhibit little or no binding. These novel isoxazole-based analogues are used in combination with SAR data from other structurally diverse inhibitors to begin constructing a pharmacophore model of the SXc- substrate binding site.","abstract_html":"Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Concentrations of L-glutamate in the CNS are regulated by a family of excitatory amino acid transporters (EAATs) that rapidly sequester and concentrate glutamate in glia and neurons, and thereby influence transmitter access to EAA receptors. In contrast to the EAAT-mediated uptake of L-Glu, the system Xc- (SXc-) transporter (an obligate exchanger of L-glutamate and L-cystine) has been implicated in the export of L-Glu from CNS cells in such a manner that it can access and activate EAA receptors. The significance of SXc- actions is reflected in the range of CNS processes including: drug addiction, brain tumor growth and oxidative protection. Recent work has focused on the synthesis of analogs and bioisosteres of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), including lipophilic analogs using lateral metalation and electrophilic quenching and their evaluations at the system xc- transporter. Bioisosteres which are not limited to amino acids were synthesized from a common intermediate. During the synthesis of hydrazone bioisosteres, most electron rich hydrazines undergo ring closer to form fused bicyclic systems, the isoxazolo[3,4-d]pyridazinones. Several hydrazone acids synthesized, bind to the SXc- with affinities comparable to those of the endogenous substrates. In contrast, the isoxazolo [3,4-d]pyridazinone analogs exhibit little or no binding. These novel isoxazole-based analogues are used in combination with SAR data from other structurally diverse inhibitors to begin constructing a pharmacophore model of the SXc- substrate binding site.","abstract_has_math":false,"creators":["RAJALE, TRIDEEP"],"institution":"University of Montana","degree_name":"Master of Science (MS)","degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-01-01T08:00:00Z","date_published":"2010-01-01T08:00:00Z","updated_at":"2026-07-24T03:12:32Z","subjects":["AMPA","Bioisosteres","Isoxazoles","L-Glutamate"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://scholarworks.umt.edu/etd/97","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["RAJALE, TRIDEEP"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:publisher","label":"Institution","values":["University of Montana"]},{"key":"dc:type","label":"Dc Type","values":["Thesis - Campus Access Only"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science (MS)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["AMPA","Bioisosteres","Isoxazoles","L-Glutamate"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarworks.umt.edu/etd/97"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Concentrations of L-glutamate in the CNS are regulated by a family of excitatory amino acid transporters (EAATs) that rapidly sequester and concentrate glutamate in glia and neurons, and thereby influence transmitter access to EAA receptors. In contrast to the EAAT-mediated uptake of L-Glu, the system Xc- (SXc-) transporter (an obligate exchanger of L-glutamate and L-cystine) has been implicated in the export of L-Glu from CNS cells in such a manner that it can access and activate EAA receptors. The significance of SXc- actions is reflected in the range of CNS processes including: drug addiction, brain tumor growth and oxidative protection. Recent work has focused on the synthesis of analogs and bioisosteres of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), including lipophilic analogs using lateral metalation and electrophilic quenching and their evaluations at the system xc- transporter. Bioisosteres which are not limited to amino acids were synthesized from a common intermediate. During the synthesis of hydrazone bioisosteres, most electron rich hydrazines undergo ring closer to form fused bicyclic systems, the isoxazolo[3,4-d]pyridazinones. Several hydrazone acids synthesized, bind to the SXc- with affinities comparable to those of the endogenous substrates. In contrast, the isoxazolo [3,4-d]pyridazinone analogs exhibit little or no binding. These novel isoxazole-based analogues are used in combination with SAR data from other structurally diverse inhibitors to begin constructing a pharmacophore model of the SXc- substrate binding site."]},{"key":"dc:title","label":"Title","values":["BIOISOSTERES OF AMPA: CONFORMATIONAL ANALYSIS AND STRUCTURE ACTIVITY RELATIONSHIP"]}]}],"canonical_facts":{"dc:creator":["RAJALE, TRIDEEP"],"dc:description.abstract":["Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Concentrations of L-glutamate in the CNS are regulated by a family of excitatory amino acid transporters (EAATs) that rapidly sequester and concentrate glutamate in glia and neurons, and thereby influence transmitter access to EAA receptors. In contrast to the EAAT-mediated uptake of L-Glu, the system Xc- (SXc-) transporter (an obligate exchanger of L-glutamate and L-cystine) has been implicated in the export of L-Glu from CNS cells in such a manner that it can access and activate EAA receptors. The significance of SXc- actions is reflected in the range of CNS processes including: drug addiction, brain tumor growth and oxidative protection. Recent work has focused on the synthesis of analogs and bioisosteres of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), including lipophilic analogs using lateral metalation and electrophilic quenching and their evaluations at the system xc- transporter. Bioisosteres which are not limited to amino acids were synthesized from a common intermediate. During the synthesis of hydrazone bioisosteres, most electron rich hydrazines undergo ring closer to form fused bicyclic systems, the isoxazolo[3,4-d]pyridazinones. Several hydrazone acids synthesized, bind to the SXc- with affinities comparable to those of the endogenous substrates. In contrast, the isoxazolo [3,4-d]pyridazinone analogs exhibit little or no binding. These novel isoxazole-based analogues are used in combination with SAR data from other structurally diverse inhibitors to begin constructing a pharmacophore model of the SXc- substrate binding site."],"dc:identifier":["https://scholarworks.umt.edu/etd/97"],"dc:publisher":["University of Montana"],"dc:subject":["AMPA","Bioisosteres","Isoxazoles","L-Glutamate"],"dc:title":["BIOISOSTERES OF AMPA: CONFORMATIONAL ANALYSIS AND STRUCTURE ACTIVITY RELATIONSHIP"],"dc:type":["Thesis - Campus Access Only"],"thesis:degree_name":["Master of Science (MS)"]},"updated_at":"2026-07-24T03:12:32Z"}