Pharmacological regulation of the phencyclidine‐binding site associated with the N‐methyl‐D‐Aspartate receptor‐operated ion channel

The ion channel operated by N‐methyl‐D‐aspartate (NMDA) receptor agonists is modified by several positive and negative effectors. A variety of chemical structures are known to antagonize the effects of NMDA agonists by preferentially binding with high affinity to the open state of the ion channel. Binding of two of these noncompetitive antagonists has been study extensively in recent months as a probe of NMDA receptor function. It has been found that NMDA agonists and antagonists increase and decrease, respectively, the binding of ³H‐TCP or ³H‐MK‐801 by altering the affinity of the putative phencyclidine (PCP) receptor localized within the ion channel. This affinity change is presumed to be correlated with the conformational change associated with channel opening. This model is also discussed in relationship to one in which binding is increased under nonequilibrium conditions because of a simple increased accessibility to the channel binding site. The modulatory effects of glycine, other amino acids, certain polyamines, and divalent cations on ³H‐TCP and/or ³H‐MK‐801 binding are discussed in relation to their effects on NMDA function in more intact, physiological preparations. It is concluded that the complexity of NMDA receptor regulation provides many possibilities for pharmacological intervention, and that the use of noncompetitive antagonists to probe NMDA receptor function could play a key role in drug development.