This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The term privileged structure refers to certain molecular scaffolds that appear to be capable of binding to multiple receptor targets, and consequently with appropriate structure modifications, could exhibit multiple activities. The isoxazole ring plays several roles in medicinal chemistry: prodrug, bioisostere, spacer, and several examples of isoxazole containing drugs are in general medical practice. We are developing synthetic methodology to apply the isoxazole scaffold to significant problems in medicinal chemistry. Our most encouraging progress in our hypothesis-driven Structure-based drug design has been made in (1) neurotransmitter analogs for the treatment for neurological disorders, (2) the SAR of Anti-hypertensive calcium channel antagonists of the nifedipine class, and (3) anti-cancer agents that target G-4 DNA conformation in the c-myc oncogene. Isoxazoles provide conformational restriction in the case of AMPA (Amino Methyl isoxazole Propionic Acid) and its analogs, which are glutamate receptor ligands which have proved important in defining sub-type specificity of this important neurotransmitter. We have developed what we believe to be the first catalytic asymmetric synthesis of AMPA analogs, and have discovered an SAR (Structure Activity Relationship) distinction between the GluR2 receptor and System XC- transporter. The isoxazole serves a function as a bioisostere in our studies of 4-isoxazolyl-1,4-dihydropyridine (ID) calcium channel blockers, wherein we have observed both robust calcium channel activity (single digit nanomolar), as well as a pronounced enantioselectivity of action. We have uncovered a unique SAR for the IDs, and have developed a drug-receptor model as a working hypothesis. Our most recent synthetic studies have focused on the covalent attachment of fluorophores to the ID scaffold, to study the structural dynamics of the calcium channel. A new class of compounds developed in our lab, exemplified by NCS 694332, use the isoxazole as a linchpin to both connect DNA interactive groups and arrange them in a precise conformation in three dimensions. NSC 694332 was found to exhibit single digit micromolar inhibition of a dozen tumor cell lines in the National Cancer Institute's (NCI) screening protocol, and selected by the NCI's Biological Evaluation Committee for in vivo screening. We have developed a working hypothesis that G-4 DNA represents the molecular target, and have obtained evidence supporting that hypothesis. We are applying synthetic methodology in our labs to other drug discovery endeavors, and have made preliminary progress in the Type 2 diabetes and infectious disease arenas.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015583-08
Application #
7609808
Study Section
Special Emphasis Panel (ZRR1-RI-8 (02))
Project Start
2007-05-01
Project End
2008-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
8
Fiscal Year
2007
Total Cost
$194,710
Indirect Cost
Name
University of Montana
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
010379790
City
Missoula
State
MT
Country
United States
Zip Code
59812
Gates, Christina; Backos, Donald S; Reigan, Philip et al. (2018) Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4. Bioorg Med Chem 26:4797-4803
Bayat Mokhtari, Elham; Lawrence, J Josh; Stone, Emily F (2018) Data Driven Models of Short-Term Synaptic Plasticity. Front Comput Neurosci 12:32
Gupta, Tarun; Morgan, Hannah R; Andrews, Jonathan C et al. (2017) Methyl-CpG binding domain proteins inhibit interspecies courtship and promote aggression in Drosophila. Sci Rep 7:5420
Steiger, Scott A; Li, Chun; Backos, Donald S et al. (2017) Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter. Bioorg Med Chem 25:3223-3234
Stine, Jessica M; Ahl, Gabriel J H; Schlenker, Casey et al. (2017) The Interaction between the Third Type III Domain from Fibronectin and Anastellin Involves ?-Strand Exchange. Biochemistry 56:4667-4675
Park, Sunyoung; Nevin, Andrew B C; Cardozo-Pelaez, Fernando et al. (2016) Pb exposure prolongs the time period for postnatal transient uptake of 5-HT by murine LSO neurons. Neurotoxicology 57:258-269
Gábriel, Robert; Erdélyi, Ferenc; Szabó, Gábor et al. (2016) Ectopic transgene expression in the retina of four transgenic mouse lines. Brain Struct Funct 221:3729-41
Gupta, T; Morgan, H R; Bailey, J A et al. (2016) Functional conservation of MBD proteins: MeCP2 and Drosophila MBD proteins alter sleep. Genes Brain Behav 15:757-774
Steiger, Scott A; Li, Chun; Campana, Charles F et al. (2016) Lanthanide and asymmetric catalyzed syntheses of sterically hindered 4-isoxazolyl-1,4-dihydropyridines and 4-isoxazolyl-quinolones. Tetrahedron Lett 57:423-425
Beske, Phillip H; Byrnes, Nicole M; Astruc-Diaz, Fanny et al. (2015) Identification of NADPH oxidase as a key mediator in the post-ischemia-induced sequestration and degradation of the GluA2 AMPA receptor subunit. J Neurochem 132:504-19

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