title: Agonist-like character of the (R)-enantiomer of 1-hydroxy-3-amino-pyrrolid-2-one (HA-966).
abstract: 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.
authors.affiliation: Department of Pharmacology, ICI Pharmaceuticals, ICI Americas Inc., Wilmington, DE 19897.
authors.forename: L M
authors.initials: LM
authors.lastname: Pullan
authors.forename: A M
authors.initials: AM
authors.lastname: Verticelli
authors.forename: K A
authors.initials: KA
authors.lastname: Paschetto
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000737:chemistry / Q000378:metabolism*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013096:Spermine / Q000494:pharmacology*; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D000598:Amino Acids, Cyclic; D011760:Pyrrolidinones; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; C023863:1-aminocyclopropane-1-carboxylic acid; C056723:FG 9041; C001369:1-hydroxy-3-amino-2-pyrrolidone; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D005998:Glycine