Abstract

Glutamate receptors are important in the transmision of signals across the synapses between nerve cells. Isoxazoles such as Amino-Methyl-Isoxazole Propionic Acid (AMPA) have been found to be useful in the characterization of Glutamate receptor subtypes. We have obtained results in the first granting period which show promise for the efficient preparation of chiral isoxazole glutamate receptor ligands. In the current granting period we propose (1) to complete the synthesis of a defined set of C(5) functionalized AMPA analogues based on structure based design using the G1uR2 subtype binding domain, (2) prepare linked antagonists and agonists to probe the Gouaux Glutamate receptor Activation and Antagonism model and (3) prepare glutamate receptor ligands covalently linked to molecular probes to help elucidate the conformation dynamics of the intact membrane bound receptor during activation and modulation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
3R15NS038444-02S1
Application #
7023621
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Silberberg, Shai D
Project Start
1999-05-01
Project End
2006-12-31
Budget Start
2002-07-01
Budget End
2006-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$30,903
Indirect Cost

  Institution

Name
University of Idaho
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
075746271
City
Moscow
State
ID
Country
United States
Zip Code
83844

  Publications

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
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
Weaver, Matthew J; Kearns, Alison K; Stump, Sascha et al. (2015) AIMing towards improved antitumor efficacy. Bioorg Med Chem Lett 25:1765-1770
Szabon-Watola, Monika I; Ulatowski, Sarah V; George, Kathleen M et al. (2014) Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model. Bioorg Med Chem Lett 24:117-21
Matti, Afnan A; Mirzaei, Joseph; Rudolph, John et al. (2013) Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model. Bioorg Med Chem Lett 23:5931-5
Mirzaei, Yousef R; Weaver, Matthew J; Steiger, Scott A et al. (2012) Improved synthesis of 3-aryl isoxazoles containing fused aromatic rings. Tetrahedron 68:10360-10364
Hulubei, Victoria; Meikrantz, Scott B; Quincy, David A et al. (2012) 4-Isoxazolyl-1,4-dihydropyridines exhibit binding at the multidrug-resistance transporter. Bioorg Med Chem 20:6613-20
Patel, Sarjubhai A; Rajale, Trideep; O'Brien, Erin et al. (2010) Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model. Bioorg Med Chem 18:202-13
Gajewski, Mariusz P; Beall, Howard; Schnieder, Mark et al. (2009) Bis-anthracenyl isoxazolyl amides have enhanced anticancer activity. Bioorg Med Chem Lett 19:4067-9
Han, Xiaochun; Li, Chun; Mosher, Michael D et al. (2009) Design, synthesis and biological evaluation of a novel class of anticancer agents: anthracenylisoxazole lexitropsin conjugates. Bioorg Med Chem 17:1671-80

Showing the most recent 10 out of 15 publications