A novel glycine site-specific N-methyl-D-aspartate receptor antagonist prevents activation of the NMDA/NO/CGMP pathway by ammonia.

Intrastriatal administration of ammonium ions ("ammonia") via a microdialysis probe overactivates N-methyl-D-aspartate (NMDA) receptors, which results in cGMP accumulation in the microdialysates. Co-administration of a potent glycine site-specific NMDA receptor antagonist CGP 78608 ([(1S)-1-[[(7-bromo-1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]amino]ethyl]phosphonate) significantly reduced (at 20 nM) or abolished (at 100 nM) ammonia-dependent cGMP synthesis. Since NMDA receptor activation is an important causative factor in ammonia neurotoxicity, the present results suggest the glycine site of the receptor to be a potential valuable target for protective intervention.