Hydrogen-bond patterns in 1,4-dihydro-2,3-quinoxalinediones: ligands for the glycine modulatory site on the NMDA receptor.
The crystal structures of five 1, 4-dihydro-2, 3-quinoxalinediones, antagonists of the NMDA modulatory glycine binding site on the excitary amino acid (EAA) receptor complex, have been determined: (I) 6, 7-dinitro-1, 4-dihydro-2, 3-quinoxalinedione (DNQX); (II) 5, 7-dinitro-1,4-dihydro-2, 3-quinoxalinedione (MNQX); (III) 6-nitro-1,4-dihydro-2, 3-quinoxalinedione hydrate; (IV) 6, 7-dichloro-1, 4-dihydro-2, 3-quinoxalinedione; (V) 5, 7-dichloro-I, 4-dihydro-2, 3-quinoxalinedione dimethylformamide. The crystal structure of the most active compound (II) contains a unique intramolecular N--H...O(NO2) hydrogen bond, which may be important for activity, as semiempirical calculations show that this bond is stable over a wide range of dihedral angles between the planes of the molecule and of the nitro group. In the other compounds the intermolecular hydrogen bonds connect molecules into three-dimensional networks. In compounds (I), (III) and (IV) head-to-tail pi-stacking is found between molecules connected by a center of symmetry. The geometries of the hydrogen-bonded -NH-C = O fragments show evidence of pi-cooperativity or resonance-assisted hydrogen bonding. Graph-set analysis of the hydrogen-bond patterns of quinoxalinedione derivatives shows a tendency to form two types of hydrogen-bonding motifs: a centrosymmetric dimeric ring and an infinite chain. Even though this pattern may be modified by the presence of additional hydrogen-bond acceptors and/or donors, as well as by solvent molecules, general similarities have been found. Comparison of all quinoxalinedione structures suggests that the hydrogen-bonding pattern necessary for the biological activity at the glycine binding site contains one donor and two acceptors.
Kubicki
M
M
Department of Chemistry, University of Calgary, Alberta, Canada.
Kindopp
T W
TW
Capparelli
M V
MV
Codding
P W
PW
D000927:Anticonvulsants / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005998:Glycine / Q000378:metabolism*; D006860:Hydrogen Bonding; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D000927:Anticonvulsants; D008024:Ligands; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C063295:5,7-dinitroquinoxaline-2,3-dione; C056723:FG 9041; D005998:Glycine