OL-1-YL)-7-NITRO-4(5H)-IMIDAZO[1,2-A]QUINOXALINONE AND RELATED-COMPOUNDS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE AMPA-TYPENON-NMDA RECEPTOR
J. Ohmori et al., OL-1-YL)-7-NITRO-4(5H)-IMIDAZO[1,2-A]QUINOXALINONE AND RELATED-COMPOUNDS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE AMPA-TYPENON-NMDA RECEPTOR, Journal of medicinal chemistry, 40(13), 1997, pp. 2053-2063
As a part of our program to discover novel antagonists for the AMPA su
btype of EAA receptors, we designed and synthesized a series of hetero
cyclic-fused imidazolylquinoxalinones 5a-c, 9, 11, 14a-e, and 18 which
led from imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochlo
ride (1a . HCl, YM90K) by replacement of its amide with the imidazole
and triazole rings. Their activity was evaluated by inhibiting [H-3]AM
PA binding from rat whole brain. As a result, it appeared that 8-(1H-i
midazol-1-yl)-7-nitro-4(5H)-imidadazo[1 ,2-a]quinoxalinone (5a) and it
s [1,2,4]triazolo[4,3-a] analogue 14a possessed high affinity for AMPA
receptors with K-i values of 0.057 and 0.19 mu M, respectively, simil
ar to the activity of 1a and NBQX (2) (1a, K-i = 0.084 mu M; 2, K-i =
0.060 mu M). In contrast, 8-(1H-imidazol-1-yl)-7-nitro-4(5H)-imidazo[1
,5- a]quinoxalinone (5b) and -8-nitro-4(5H)-[1,2,4]triazolo[4,3-a]quin
oxalinone (18) showed no or weak affinity for the receptors. Hence, we
deduced that the nitrogen atom of the fused heterocycles at the 3-pos
ition of 5a and 14a plays an essential role as hydrogen bond accepters
in binding to AMPA receptors, whereas their amides act as proton dono
rs. From the SAR on 1-alkyl derivatives of 5a and 14a, it was indicate
d that introduction of suitable 1-alkyl substituents led to a severalf
old improved AMPA affinity. A computational study on a model of water-
quinoxaline complexes, a mimic of the putative hydrogen-bonding intera
ction between the receptors and quinoxalines, indicated that the diffe
rent affinities of 5a, 14a, la, and 19 for the AMPA receptor may depen
d 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 heterocycli
c-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 mu M, respectively (1a, 0.81 mu M; 2, 0.38 mu M).
Moreover 5a possesses over 5000-fold AMPA selectivity against both th
e NMDA receptor and the glycine site on the NMDA receptor.