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.
Ohmori
J
J
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Company Limited, Ibaraki, Japan.
Shimizu-Sasamata
M
M
Okada
M
M
Sakamoto
S
S
D000818:Animals; D001921:Brain / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006900:Hydroxylation; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
C101729:1-hydroxy-7-(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)-quinoxalinedione; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D011810:Quinoxalines; D018091:Receptors, AMPA; D014316:Tritium; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid