Abstract

As the primary excitatory neurotransmitter in the mammalian central nervous system, glutamate mediates signaling between neurons by activating at least five different types of membrane bound receptors. Characterizing these receptors is a top priority not only because of their function in normal processes such as learning and memory, but also due to their role in causing damage in pathological states such as ischemia, stroke, epilepsy, and Alzheimer's disease. The general goals of this project are to provide a better understanding of the molecular interactions that control these processes, and to obtain new evidence on the structures of the receptors themselves. Continuing structure-activity studies of """"""""rigidified"""""""" glutamate analogues are intended to further our knowledge of receptor binding site preferences. In addition, new models of the three-dimension structures of several of the receptors are to be tested with proposed photoaffinity probes and de novo designed ligands. The ultimate goal is a complete understanding at the molecular level of agonist and antagonist action at each receptor type, which could ultimately lead to the improved design of CNS drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027600-10
Application #
6393444
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Chiu, Arlene Y
Project Start
1990-09-20
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
10
Fiscal Year
2001
Total Cost
$201,059
Indirect Cost

  Institution

Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697

  Publications

Gennarino, Vincenzo A; Singh, Ravi K; White, Joshua J et al. (2015) Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. Cell 160:1087-98
Carroll, Christopher L; Chamberlin, A Richard (2011) Synthesis of the dysiherbaine tetrahydropyran core utilizing improved tethered aminohydroxylation conditions. Tetrahedron Lett 52:3995-3997
Limon, Agenor; Reyes-Ruiz, Jorge M; Vaswani, Rishi G et al. (2010) Kaitocephalin antagonism of glutamate receptors expressed in Xenopus oocytes. ACS Chem Neurosci 1:175-181
Vaswani, Rishi G; Limon, Agenor; Reyes-Ruiz, Jorge Mauricio et al. (2009) Design, synthesis, and biological evaluation of a scaffold for iGluR ligands based on the structure of (-)-kaitocephalin. Bioorg Med Chem Lett 19:132-5
Okamura, Naoe; Habay, Stephen A; Zeng, Joanne et al. (2008) Synthesis and pharmacological in vitro and in vivo profile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the neuropeptide S receptor. J Pharmacol Exp Ther 325:893-901
Vaswani, Rishi G; Chamberlin, A Richard (2008) Stereocontrolled total synthesis of (--)-kaitocephalin. J Org Chem 73:1661-81
Cohen, Jamie L; Chamberlin, A Richard (2007) Synthesis of the dysiherbaine tetrahydropyran core employing a tethered aminohydroxylation reaction. Tetrahedron Lett 48:2533-2536
Cohen, Jamie L; Chamberlin, A Richard (2007) Diastereoselective synthesis of glutamate-appended oxolane rings: synthesis of (s)-(+)-lycoperdic acid. J Org Chem 72:9240-7
Cohen, Jamie L; Limon, Agenor; Miledi, Ricardo et al. (2006) Design, synthesis, and biological evaluation of a scaffold for iGluR ligands based on the structure of (-)-dysiherbaine. Bioorg Med Chem Lett 16:2189-94
Esslinger, C Sean; Agarwal, Shailesh; Gerdes, John et al. (2005) The substituted aspartate analogue L-beta-threo-benzyl-aspartate preferentially inhibits the neuronal excitatory amino acid transporter EAAT3. Neuropharmacology 49:850-61

Showing the most recent 10 out of 26 publications