8-(1H-imidazol-1-yl)-7-nitro-4(5H)-imidazo[1,2-alpha]quinoxalinone and related compounds: synthesis and structure-activity relationships for the AMPA-type non-NMDA receptor.
As a part of our program to discover novel antagonists for the AMPA subtype of EAA receptors, we designed and synthesized a series of heterocyclic-fused imidazolylquinoxalinones 5a-c, 9, 11, 14a-e, and 18 which led from 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (1a.HCl, YM90K) by replacement of its amide with the imidazole and triazole rings. Their activity was evaluated by inhibiting [3H]AMPA binding from rat whole brain. As a result, it appeared that 8-(1H-imidazol-1-yl)-7-nitro-4(5H)-imidazo[1,2-alpha]quinoxalinone (5a) and its [1,2,4]triazolo[4,3-alpha] analogue 14a possessed high affinity for AMPA receptors with Ki values of 0.057 and 0.19 microM, respectively, similar to the activity of 1a and NBQX (2) (1a, Ki = 0.084 microM; 2, Ki = 0.060 microM). In contrast, 8-(1H-imidazol-1-yl)-7-nitro-4(5H)-imidazo[1,5-alpha]quinoxalinone (5b) and 7-(1H-imidazol-1-yl)-8-nitro-4(5H)-[1,2,4]triazolo[4,3-alpha]quinoxalino ne (18) showed no or weak affinity for the receptors. Hence, we deduced that the nitrogen atom of the fused heterocycles at the 3-position of 5a and 14a plays an essential role as hydrogen bond acceptors in binding to AMPA receptors, whereas their amides act as proton donors. From the SAR on 1-alkyl derivatives of 5a and 14a, it was indicated that introduction of suitable 1-alkyl substituents led to a severalfold improved AMPA affinity. A computational study on a model of water-quinoxaline complexes, a mimic of the putative hydrogen-bonding interaction between the receptors and quinoxalines, indicated that the different affinities of 5a, 14a, 1a, and 19 for the AMPA receptor may depend on, at least in part, each stabilization energy for the interaction. On this basis, we propose a pharmacophore model of AMPA receptors for the binding of the imidazolylquinoxaline derivatives. The heterocyclic-fused quinoxalinones 5a,c and 9 showed potent inhibitory activity in KA-induced toxicity for hippocampal cell culture with IC50 values of 0.30, 0.32, and 0.30 microM, respectively (1a, 0.81 microM; 2, 0.38 microM). Moreover 5a possesses over 5000-fold AMPA selectivity against both the NMDA receptor and the glycine site on the 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; D001667:Binding, Competitive; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
C107011:8-(1H-imidazol-1-yl)-7-nitro-4(5H)-imidazo(1,2-a)quinoxalinone; D007093:Imidazoles; D008024:Ligands; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid