title: Characterization of a novel putative cognition enhancer mediating facilitation of glycine effect on strychnine-resistant sites coupled to NMDA receptor complex.
abstract: The effects of (S)-4-amino-5-[(4,4-dimethylcyclohexyl)amino]-5-oxo-pentanoic acid ((S)CR 2249), a new chemical entity selected among a series of glutamic acid derivatives, were investigated on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline from rat hippocampal slices. (S)CR 2249 facilitated glycine-mediated reversion of kynurenate antagonism at strychnine-insensitive glycine receptors coupled to the NMDA receptor. The potency of glycine (EC50 = 21.5 microM +/- 4.2) was not significantly influenced by (S)CR 2249. Nevertheless, the efficacy of the glycine effect was enhanced in a concentration-dependent manner (3-10-30 microm) by (S)CR 2249. The interaction of (S)CR 2249 with NMDA receptors was also studied with binding experiments, in which we examined the effect of (S)CR 2249 on the modulation by glutamate, glycine and spermine of [3H]dizocilpine (MK-801) binding. (S)CR 2249, increased [3H]MK-801 binding in a concentration-dependent manner and we found positive cooperative interactions between glycine and (S)CR 2249, indicating that (S)CR 2249 probably acts at a separate allosteric site to increase NMDA receptor functionality.
authors.affiliation: Rotta Research Laboratorium S.p.A., Monza (MI), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Lanza
authors.forename: C
authors.initials: C
authors.lastname: Bonnafous
authors.forename: S
authors.initials: S
authors.lastname: Colombo
authors.forename: L
authors.initials: L
authors.lastname: Revel
authors.forename: F
authors.initials: F
authors.lastname: Makovec
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013096:Spermine / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D018690:Excitatory Amino Acid Agonists; D018697:Nootropic Agents; D010421:Pentanoic Acids; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C105010:neboglamine; D013096:Spermine; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D005998:Glycine; D009638:Norepinephrine