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]pyrazin-5-yl) acetic acid) was previously reported to exhibit potent affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor-channel complex in the nanomolar range (K(i)=3.1+/-0. 8 nM). We now report on the effects of RPR 118723 in two functional tests reflecting the interaction between the glycine site and the NMDA receptor. First, RPR 118723 potently inhibited [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP) binding in the presence of NMDA (IC(50)=3.5+/-0.4 nM). Second, RPR 118723 antagonized the NMDA-induced increase in [3H]dopamine release in mouse striatal slices (IC(50)=8.0+/-1.1 nM). In both experimental models, an excess of glycine reversed the effect of RPR 118723. These results show that RPR 118723 interferes functionally in the nanomolar range with the glycine site coupled to the NMDA receptor in vitro. The blockade of the glycine site with RPR 118723 may be useful for the therapy of the disorders linked to excessive NMDA stimulation.
Boireau
A
A
Aventis Pharma S.A., Centre de Recherche de Vitry-Alfortville, 13, quai Jules Guesde, BP 14, 94403 Cedex, Vitry-sur-Seine, France.
Monterrat
C
C
Bordier
F
F
Meunier
M
M
Imperato
A
A
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014316:Tritium
D018691:Excitatory Amino Acid Antagonists; D011719:Pyrazines; C410936:RPR 118723; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016202:N-Methylaspartate; C012058:tenocyclidine; D010622:Phencyclidine; D005998:Glycine; D004298:Dopamine