Novel AMPA Receptor Antagonists: Synthesis and Structure−Activity Relationships of 1-Hydroxy-7-(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)- quinoxalinedione and Related Compounds

As part of our study of novel antagonists at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtype of excitatory amino acid (EAA) receptors and the pharmacophoric requirements of the receptor, we designed and synthesized a series of 1-substituted 6-imidazolyl-7-nitro-, and 7-imidazolyl-6-nitroquinoxalinediones, as well as related compounds, 6a-j, 7, 11a-e, 15, and 17, which are 1- and 4-substituted analogues of 1 (YM90K), and evaluated their activity to inhibit [3H]AMPA binding from rat whole brain. On the basis of their structure-activity relationships (SAR), we deduced that the amide proton of the imidazolyl-near side of the quinoxalinedione nucleus is not essential for AMPA receptor binding, whereas that of the imidazolyl-far amide is. Further, the receptors possess size-limited bulk tolerance for their N-substituents on the imidazolyl-near amide portion. Moreover, we found that introduction of a hydroxyl group at the imidazolyl-near amide portion causes a severalfold improvement in AMPA receptor affinity over unsubstituted derivatives. Among the compounds, 1-hydroxy-7-(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)-quinoxalinedione (11a) showed high affinity for AMPA receptor with a Ki value of 0.021 microM, which is severalfold greater than that of 1 and NBQX (2) (1,Ki = 0.084 microM; 2,Ki = 0.060 microM). Compound 11a also showed over 100-fold selectivity for the AMPA receptor than for the N-methyl-D-aspartate (NMDA) receptor and the glycine site on NMDA receptor.