NOVEL AMPA RECEPTOR ANTAGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF IMIDAZOL-1-YL)-6-NITRO-2,3(1H,4H)-QUINOXALINEDIONE AND RELATED-COMPOUNDS

As part of our study of novel antagonists at the pha-amino-3-hydroxy-5 -methylisoxazole-4-propionate (AMPA) subtype of excitatory amino acid (EAA) receptors and the pharmacophoric requirements of the receptor, w e designed and synthesized a series of 1-substituted 6-imidazolyl-7-ni tro-, and 7-imidazolyl-6-nitroquinoxalinediones, as well as related co mpounds, 6a-j, 7, 11a-e, 15, and 17, which are 1- and 4-substituted an alogues of 1 (YM90K), and evaluated their activity to inhibit [H-3]AMP A binding from rat whole brain. On the basis of their structure-activi ty relationships (SAR), we deduced that the amide proton of the imidaz olyl-near side of the quinoxalinedione nucleus is not essential for AM PA receptor binding, whereas that of the imidazolyl-far amide is. Furt her, the receptors possess size-limited bulk tolerance for their N-sub stituents on the imidazolyl-near amide portion. Moreover, we found tha t introduction of a hydroxyl group at the imidazolyl-near amide portio n causes a severalfold improvement in AMPA receptor affinity over unsu bstituted derivatives. Among the compounds, -(1H-imidazol-1-yl)-6-nitr o-2,3(1H,4H)-quinoxaline dione (11a) showed high affinity for AMPA rec eptor with a K-i value of 0.021 mu M, which is severalfold greater tha n that of 1 and NBQX (2) (1, K-i = 0.084 mu M; 2, K-i = 0.060 mu M). C ompound 11a also showed over 100-fold selectivity for the AMPA recepto r than for the N-methyl-D-aspartate (NMDA) receptor and the glycine si te on NMDA receptor.