fg-9041 and 1-hydroxy-3-amino-2-pyrrolidone

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Binding Sites; Cognition; Glycine; Humans; Kynurenic Acid; Neuroprotective Agents; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

HA-966 (1-hydroxy-3-amino-pyrrolid-2-one), an antagonist at the strychnine-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 IC50 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 binding site. The IC50 values of the agonist glycine and the partial agonist 1-aminocyclopropane-1-carboxylate are also decreased. The IC50 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.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Binding, Competitive; Dose-Response Relationship, Drug; Glycine; Kynurenic Acid; Male; Pyrrolidinones; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Spermine; Stereoisomerism; Synaptosomes

Direct intracerebellar administration of quisqualate resulted in marked increases in levels of cGMP in the cerebellum of the mouse, with a Hill number of 2.0. Quinoxalinediones, DNQX (6,7-dinitroquinoxaline-2,3-dione) and CNQX (6-nitro,7-cyanoquinoxaline-2,3-dione) attenuated the quisqualate-induced response. 6,7-Dinitroquinoxaline-2,3-dione also attenuated the D-serine-induced increases in levels of cGMP in a competitive manner. Intracerebellar injection of DNQX also antagonized the response to parenterally-administered harmaline. Similar results were also obtained with CNQX. These results indicate that these quinoxalinediones can attenuate the responses, mediated through the NMDA-associated glycine recognition sites, as well as the NMDA receptor complex. However, the glycine antagonist HA-966 (3-amino-1-hydroxypyrrolidone-2), at doses which completely reversed the increases induced by D-serine, failed to alter the response to quisqualate, indicating a lack of effect of glycine antagonists on quisqualate-mediated synaptic events. These results further support the interaction of the quinoxalinediones, DNQX and CNQX, with the NMDA receptor complex as established in receptor binding and electrophysiological studies.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cerebellum; Cyclic AMP; Glycine; Harmaline; Kinetics; Male; Mice; N-Methylaspartate; Pyrrolidinones; Quinoxalines; Quisqualic Acid; Serine