The NMDA(N-methyl-D-aspartate) receptor has been strongly implemented in the fundamental biochemical events concerning memory and learning. This receptor serve as an important element in the induction of long term potentiation (LTP), a phenomenon believed to provide a possible mechanism for information storage. Central to this grant application is the fact that phencyclidine (PCP) has been shown to function as a negative allosteric modulator of the NMDA receptor as determined by various electrophysiological, radioligard binding, and biochemical experiments. PCP is capable, for example, of inhibiting 45Ca++ uptake induced by glutamate at the NMDA receptor. It is our aim to discover through a synthesis and biological testing program PCP-based compounds capable of functioning as positive allosteric modulators of the NMDA receptor. Such agents should prove extremely useful as biochemical tools for further characterizing the events of signal transduction at the NMDA receptor. Such compounds could furthermore possible function in man as cognition enhancing agents. Moreover, through chemical alterations of PCP involving the synthesis of structurally rigid analogues, it is our aim to learn more about the conformation of this small molecule when bound to its receptor as well as to better understand the topography of the receptor itself. The synthesis and testing of the structurally rigid PCP analogues may possibly lead to the discovery of a pure antagonist of PCP action. The characterization of a compound capable of binding tightly to the PCP receptor but incapable of eliciting a biochemical response may find use as an antidote for PCP overdose, or if labeled as an agent for imaging NMDA receptors in vivo by PET. Since an endogenous peptide ligand of the PCP receptor possessing PCP-like effects has been identified, an antagonist find use in disease states associated with depression of activity at the NMDA sites. The synthesis-biochemical-behavioral testing program to be pursued should greatly expand our understanding at the molecular level of the PCP-NMDA receptor/receptor coupling.
