CHARACTERIZATION OF A NOVEL PUTATIVE COGNITION ENHANCER MEDIATING FACILITATION OF GLYCINE EFFECT ON STRYCHNINE-RESISTANT SITES COUPLED TO NMDA RECEPTOR-COMPLEX

The effects of o-5-[(4,4-dimethylcyclohexyl)amino]-5-oxo-petanoic acid ((S)CR 2249), a new chemical entity selected among a series of glutam ic acid derivatives, were investigated on N-methyl-D-aspartate (NMDA)- evoked release of [H-3]noradrenaline from rat hippocampal slices. (S)C R 2249 facilitated glycine-mediated reversion of kynurenate antagonism at strychnine-insensitive glycine receptors coupled to the NMDA recep tor. The potency of glycine (EC50 = 21.5 mu M +/- 4.2) was not signifi cantly influenced by (S)CR 2249. Nevertheless, the efficacy of the gly cine effect was enhanced in a concentration-dependent manner (3-10-30 mu m) by (S)CR 2249. The interaction of (S)CR 2249 with NMDA receptors was also studied with binding experiments, in which we examined the e ffect of (S)CR 2249 on the modulation by glutamate, glycine and spermi ne of [H-3]dizocilpine (MK-801) binding. (S)CR 2249, increased [H-3]MK -801 binding in a concentration-dependent manner and we found positive cooperative interactions between glycine and (S)CR 2249, indicating t hat (S)CR 2249 probably acts at a separate allosteric site to increase NMDA receptor functionality. (C) 1997 Elsevier Science Ltd.