NOVEL PHA-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONATE RECEPTOR ANTAGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF -YL)-7-NITRO-2,3(1H,4H)-PYRIDO[2,3-B]PYRAZINEDIONE AND RELATED-COMPOUNDS

We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [H-3]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure- activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2, 3-b]pyrazinedione derivatives 4, 7-10, 13, 15, and 16 showed some diff erences in comparison with those of the corresponding substituted quin oxalinediones, including imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxaline dione (1) (YM90K). The X-ray study exhibited that conformation of the 7-nitro group of 1 . HCl was nearly coplanar with the quinoxaline ring , whereas the 6-imidazol-1-yl group was rotated with respect to the ar omatic ring. From the glycine site on NMDA receptor binding study, it is indicated that bulkiness of 6-substituents on pyridopyrazinediones may be responsible for the selectivity against the glycine site. Among the series of azaquinoxalinediones, -yl)-7-nitro-2,3(1H,4H)-pyrido[2, 3-b]pyrazinedione (8c) exhibited a combination of the best affinity to the AMPA receptors with a K-i value of 0.14 mu M and selectivity agai nst the glycine site (no affinity at 10 mu M). In vivo, 8c also protec ted against sound-induced seizure in DBA/2 mice (minimum effective dos e, 10 mg/kg ip).