Excitatory amino acid-induced toxicity has been implicated in the nerve cell loss associated with several significant clinical conditions, including stroke, mechanical trauma to the nervous system, amyotrophic lateral sclerosis, and epilepsy. Strategies aimed at reducing this excitotoxicity have focused on blocking excitatory amino acid receptors, particularly the NMDA receptor and group I metabotropic glutamate receptors (mGluRs), activation of group II and III mGluRs, and reducing synaptic glutamate. This research program focuses on the latter two strategies to design, synthesize and test new compounds that may have therapeutic potential for the treatment of excitotoxicity. Central to this approach is N-acetylaspartylyglutamate (NAAG), the most prevalent and widely distributed peptide transmitter in the mammalian central nervous system. NAAG is a selective agonist at group II metabotropic glutamate receptors. Activation of these receptors has been shown to be neuroprotective in vitro and in vivo. NAAG and related group II agonists inhibit transmitter release by a presynaptic mechanism. Equally important, NAAG is inactivated by peptidase activity in the synaptic space to produce glutamate and N-acetylaspartate The program will extend preliminary work in which NAAG analogues with a central urea group have been synthesized and tested for their ability to inhibit enzymes that hydrolyze NAAG, particularly glutamate carboxypeptidase II (GCPII).
An aim i s to identify novel NAAG-peptidase inhibitors that will increase the peptide concentration following synaptic release, thus increasing activation of group II receptors, while decreasing the release of glutamate from NAAG. In our current SAR work, we have identified several urea-based structures that exhibit nM potency in the inhibition of this peptidase. Based upon these lead compounds, and using rational drug design, we will prepare a library of compounds that serve to further delineate structural features relevant to enhancing inhibitory potency and bioavailability. The program aims to acquire a better understanding of the typography of the enzyme active site of GCPII, and ultimately to produce compounds for use in vivo. Homology-based modeling methods will be employed to create a 3D structure of the enzyme, and the model will be used in turn to assist in ligand design. Since this drug design program has used the peptide as lead compound, it is anticipated that some of the peptidase inhibitors that are identified also may function as group II receptor agonists, an activity that would enhance their neuroprotective potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042672-02
Application #
6620494
Study Section
Special Emphasis Panel (ZRG1-SSS-Q (01))
Program Officer
Oliver, Eugene J
Project Start
2001-12-15
Project End
2005-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$481,838
Indirect Cost
Name
Georgetown University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Jayaprakash, Sarva; Wang, Xinning; Heston, Warren D et al. (2006) Design and synthesis of a PSMA inhibitor-doxorubicin conjugate for targeted prostate cancer therapy. ChemMedChem 1:299-302
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Jayaprakash, Sarva; Iso, Yasuyoshi; Wan, Baojie et al. (2006) Design, synthesis, and SAR studies of mefloquine-based ligands as potential antituberculosis agents. ChemMedChem 1:593-7
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Olszewski, Rafal T; Bukhari, Noreen; Zhou, Jia et al. (2004) NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem 89:876-85
Pomper, Martin G; Musachio, John L; Zhang, Jiazhong et al. (2002) 11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase). Mol Imaging 1:96-101

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