Journal of Medicinal Chemistry p. 3956 - 3968 (1994)
Update date:2022-07-30
Topics:
Nagata, Ryu
Tanno, Norihiko
Kodo, Toru
Ae, Nobuyuki
Yamaguchi, Hiroshi
et al.
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 (Ki = 9.9 nM) displayed high affinity for the glycine site.The anilide derivative 20g (Ki = 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 (Ki = 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 (Ki = 0.96 nM) retained the affinity among the anilide derivatives, whereas both enantiomers 23g (Ki = 2.3 nM) and 24g (Ki = 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.
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