5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition.

Abstract NMDA antagonists derived from 5-phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione ( 3a ) are potent anticonvulsant agents, and display strong protective effects in the electroshock-induced convulsion assay in mice. Their preference for the human NMDAR 1A/2A over 1A/2B subunit composition was optimized, leading to (1 RS ,1′ S )-PEAQX ( 9r ), which shows a >100-fold selectivity.