The excitatory amino acid (EAA) glutamic acid has a central role in the computer-like signaling that occurs between neurons in the nervous system. It appears to be involved both in signaling on a millisecond time scale and in slower regulatory functions. These diverse actions are mediated by at least four major classes of EAA receptors. One of those classes is the L-2-amino-4-phosphonobutanoic acid (L-AP4) receptor, named for a potent agonist for this receptor. A number of compounds structurally related to L-AP4 have shown promising properties for differentiating the L-AP4 receptor from other EAA receptors and for gaining insight into the features of molecular structure needed for molecules to interact with L-AP4 receptors.
The specific aims of this project are: (1) to synthesize novel structural analogues of L-AP4 in order to develop selective and novel pharmacological agents for differentiating AP4-sensitive biological systems; (2) to evaluate these compounds as agonists for L-AP4 receptors in selected retinal, hippocampal, and spinal neural systems; (3) to seek EAA analogues that act as antagonists for the L-AP4 receptor. Antagonists have proven to be powerful tools for pharmacological studies, but no antagonists are known for L-AP4 receptors; (4) to evaluate novel analogues of L-AP4 for their activity on other EAA receptors and on an EAA transmembrane transport system. This research is intended to provide pharmacological probes of value both for elucidating the underlying biological roles of excitatory amino acid receptors and as possible experimental and therapeutic agents for modifying neuronal signaling. These studies may have significance for understanding mechanisms of neuronal control and plasticity and may also lead to insight into changes of neuronal excitability that occur in disease states such as epilepsy.
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