Effects of RPR 118723, a novel antagonist at the glycine site of the NMDA receptor, in vitro

RPR 118723 ((8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno[1,2-b]pyrazi n-5-yl) acetic acid) was previously reported to exhibit potent affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor-channel compl ex in the nanomolar range (K-i = 3.1 +/- 0.8 nM). We nets report on the eff ects of RPR 118723 in two functional tests reflecting the interaction betwe en the glycine site and the NMDA receptor. First, RPR 118723 potently inhib ited [H-3]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([H-3]TCP) binding in the presence of NMDA (IC50 = 3.5 +/- 0.4 nM). Second, RPR 118723 antagonize d the NMDA-induced increase in [H-3]dopamine release in mouse striatal slic es (IC50 = 8.0 +/- 1.1 nM). In both experimental models, an excess of glyci ne reversed the effect of RPR 118723. These results show that RPR 118723 in terferes functionally in the nanomolar range with the glycine site coupled to the NMDA receptor in vitro. The blockade of the glycine site with RPR 11 8723 may be useful for the therapy of the disorders linked to excessive NMD A stimulation. (C) 2000 Published by Elsevier Science B.V.