Structural determinants of affinity for the phencyclidine binding site of the N-methyl-D-aspartate receptor complex: discovery of a rigid phencyclidine analogue of high binding affinity

AP Kozikowski and YP Pang

Department of Chemistry, University of Pittsburgh, Chevron Science Center, Pennsylvania 15260.

To learn more about the binding conformation of phencyclidine (PCP) and to arrive at analogues of higher affinity, which may serve as noncompetitive N-methyl-D-aspartate receptor antagonists, eight optically pure PCP analogues were designed with the aid of computer. These compounds represent conformationally constrained versions of PCP in which the motion of the phenyl ring is frozen, thus allowing a determination of the orientation of the phenyl ring relevant to binding. The analogues were synthesized by a Diels-Alder strategy and tested in a radioligand binding assay to evaluate their affinity for the PCP binding site of the N-methyl-D-aspartate receptor complex. One of the analogues was found to bind with nanomolar affinity (IC50 = 19 nM) and to be 73-fold more potent in binding than its enantiomer. These results, which further elucidate the structural determinants of high affinity binding, should aid both in the design of higher affinity molecular probes of the PCP binding site and in the discovery of potential neuroprotective agents.

Volume 37, Issue 3, pp. 352-357, 03/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics