N-methyl-D-aspartate receptors (NMDARs) are responsible for the slow component of excitatory synaptic transmission in response to co-agonist binding of glutamate and glycine. The structural view of the receptors is that they are hetero-tetrameric receptors composed of two NR1 subunits and two NR2(A-D) subunits. The differential expression patterns associated with each particular NR2 subunit type present pharmacological rationale for intervention in diseases such as Parkinson's, schizophrenia, and ischemic cell death. We have identified several distinct classes of molecules that are selective against the NR2C/NR2D receptor subtypes through a medium-throughput screening endeavor. Preliminary data suggest an overlapping binding site for two distinct classes of molecules within the S2 region of the receptor may be responsible for the non- competitive, voltage independent antagonism observed with two of the classes that have been discovered. In order to test this hypothesis, we are proposing to use chimeric receptors, computer assisted modeling, and synthetic chemistry in an effort to develop potent and selective small molecules that will allow for description of the novel binding site, as well as a pharmacophore description of the small molecules. These studies will provide first in class subunit-selective pharmacological tools that will aid in furthering our understanding of the physiological and patho-physiological roles played by different NMDA receptors.

Public Health Relevance

This project aims to develop small molecules that will allow us to begin to understand the role of particular NMDA receptor subtypes in disease states. The receptors are composed of two NR1 subunits and two NR2(A-D) subunits. The expression patterns of the different receptor combinations within the brain containing NMDA present pharmacological rationale for intervention in diseases such as Parkinson's, schizophrenia, and Alzheimer's.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS071802-03
Application #
8264556
Study Section
Special Emphasis Panel (ZRG1-F03B-H (20))
Program Officer
Silberberg, Shai D
Project Start
2010-06-23
Project End
2013-06-22
Budget Start
2012-06-23
Budget End
2013-06-22
Support Year
3
Fiscal Year
2012
Total Cost
$30,912
Indirect Cost
Name
Emory University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322