Tricyclic Quinoxalinediones: 5,6-Dihydro-1H-pyrroloquinoxaline-2,3-diones and 6,7-Dihydro-1H,5H-pyridoquinoxaline-2,3-diones as Potent Antagonists for the Glycine Binding Site of the NMDA Receptor

Article abstract of DOI:10.1021/jm00049a015

A series of tricyclic quinoxalinediones, 5,6-dihydro-1H-pyrrolo<1,2,3-de>quinoxaline-2,3-diones and 6,7-dihydro-1H,5H-pyrido<1,2,3-de>quinoxaline-2,3-diones, were synthesized and was evaluated for their affinity for the glycine binding site of the NMDA receptor using a <3H>-5,7-dichlorokynurenic acid binding assay.The six-membered ring-fused tricyclic quinoxalinedione 18g (K_i = 9.9 nM) displayed high affinity for the glycine site.The anilide derivative 20g (K_i = 2.6 nM) was 4-fold more potent than 18g and as potent as L-689,560, one of the most potent glycineantagonists so far prepared.Although the carboxylic acid derivative of the corresponding five-membered ring-fused tricyclic quinoxalinedione 18e (K_i = 7.3 nM) had affinity comparable to that of 18g, the anilide derivative 20e largely decreased in the affinity in contrast to 20g.Enantiomers 23g, 24g, 25g, and 26g were prepared and tested.Only the S enantiomer 25g (K_i = 0.96 nM) retained the affinity among the anilide 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 18e and 18g would be a charge-charge interaction between the anionic carboxylate residues of the compounds and the cationic proton-donor site in the receptor.