Agonist-like character of the (R)-enantiomer of 1-hydroxy-3-amino-pyrrolid-2-one (HA-966)

HA-966 (1-hydroxy-3-amino-pyrrolid-2-one), an antagonist at the strychine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex, only partially inhibits the binding of noncompetitive antagonists to the NMDA receptor but enhances the binding of the NMDA competitive antagonist CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid). Here we report that the IC 50 of the active (R)-enantiomer of HA-966 for displacement of [ 3H]glycine binding is decreased in the presence of spermine, suggesting that spermine increases the affinity of (R)-HA-966 at the [ 3H]glycine site. The IC 50 values of the agonist glycine and the partial agonist 1-aminocyclopropane-1-carboxyalate are also decreases. The IC 50 values of glycine antagonists, 6,7-dinitroquinoxalin-2,3-dione and 7-chlorokynurenic acid are not significantly altered. The spermine shift represents the first demonstration of the agonist-like character of the (R)-enantiomer of HA-966 at the glycine site.