The objective of this research proposal is the development of selective and potent agonists and antagonists for various subtypes of metabotropic glutamate receptors. To this end, the following potential ligands will be synthesized: (1) Conformationally constrained analogs of L-AP4 in order to develop selective agonists; (2) analogs of methyl- L-AP4 to explore the basis behind its ability to serve as antagonist; (3) Analogs of quisqualic acid in which the oxadiazolidinedione ring is replaced with different other heterocyclic ring systems to generate selective agonists or antagonists of the mGluR1 and mGluR5 receptors; and (4) Conformationally constrained analogs of quisqualic acid in various conformations. These compounds will be evaluated for their ability to serve as agonists and antagonists at specific cloned and expressed metabotropic receptors. This research is intended to result in the discovery and development of agonists and antagonists for the various subtypes of metabotropic receptors that have been discovered.
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| Chase, L A; Roon, R J; Wellman, L et al. (2001) L-Quisqualic acid transport into hippocampal neurons by a cystine-sensitive carrier is required for the induction of quisqualate sensitization. Neuroscience 106:287-301 |
| Littman, L; Tokar, C; Venkatraman, S et al. (1999) Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands. J Med Chem 42:1639-47 |
