TRICYCLIC QUINOXALINEDIONES - IHYDRO-1H-PYRROLOL[1,2,3-DE]QUINOXALINE-2,3-DIONES AND HYDRO-1H,5H-PYRIDO[1,2,3-DE]QUINOXALINE-2,3-DIONES AS POTENT ANTAGONISTS FOR THE GLYCINE BINDING-SITE OF THE NMDA RECEPTOR

A series of tricyclic quinoxalinediones, dihydro-1H-pyrrolo[1,2,3-de]q uinoxaline-2,3-diones and ydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-d iones, were synthesized and was evaluated for their affinity for the g lycine binding site of the NMDA receptor using a [H-3]- 5,7-dichloroky nurenic acid binding assay. The six-membered ring-fused tricyclic quin oxalinedione 18g (K-i = 9.9 nM) displayed high affinity for the glycin e site. The anilide derivative 20g (K-i = 2.6 nM) was 4-fold more pote nt than 18g and as potent as L-689,560, one of the most potent glycine antagonists so far prepared. Although the carboxylic acid derivative of the corresponding five-membered ring-fused tricyclic quinoxalinedio ne 18e (K-i = 7.3 nM) had affinity comparable to that of 18g, the anil ide derivative 20e largely decreased in the affinity in contrast to 20 g. Enantiomers 23g, 24g, 25g, and 26g were prepared and tested. Only t he S enantiomer 25g (K-i = 0.96 nM) retained the affinity among the an ilide derivatives, whereas both enantiomers 23g (K-i = 2.3 nM) and 24g (K-i = 9.6 nM) were active among the carboxylic acid derivatives. The origin of the high affinity of carboxylic acid derivatives such as 18 e and 18g would be a charge-charge interaction between the anionic car boxylate residues of the compounds and the cationic proton-donor site in the receptor.