Review Central & Peripheral Nervous Systems: Glycine-site NMDA receptor antagonists

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Abstract
The patent literature on antagonists for the glycine site of the NMDA receptor, covering the two years prior to July 1995, is reviewed. Compound classes reported include quinoxaline-2,3-diones; imidazolopyrazinones; triazolopyrimidones; pyridazinoquinolines; benz[b]azepine-2,5-diones; 1,2,4-benzothiadiazine-1,1-dioxides; 2-carboxyindoles; 2-quinolones; miscellaneous other compounds, and kynurenine-derived molecules. Glycine site antagonists have an improved therapeutic index relative to other classes of NMDA antagonists, and show considerable therapeutic promise for CNS disorders, including cerebral ischaemia, epilepsy, head injury and schizophrenia. However, despite apparently extensive effort, very few compounds are entering clinical development. This is probably due to the difficulty in achieving suitable in vivo activity, because antagonists with high affinity for the glycine site are mostly acidic and do not easily cross the blood-brain barrier. Glycine site antagonists with useful in vivo activity are currently limited to the N-hydroxypyr-rolidinones, R(+)-HA-966 and L-687,414 (Merck); the quinoxaline-2,3-diones, ACEA 1021 (Ciba/CoCensys) and SM-18400 (Sumitomo); and the 4-hydroxy-2-quinolone, L-701,324 (Merck).

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