fg-9041 and 5-7-dinitroquinoxaline-2-3-dione

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.

Topics: Anticonvulsants; Binding Sites; Crystallography, X-Ray; Glycine; Hydrogen Bonding; Ligands; Molecular Conformation; Molecular Structure; Quinoxalines; Receptors, N-Methyl-D-Aspartate

gamma-L-Glutamylglutamate (LGG), an endogenous constituent of the brain, reduced the glutamate-evoked increase in intracellular Ca2+ in cultured cerebellar granule cells. The extent and properties of this inhibition were different at different Mg2+ concentrations. The intracellular Ca2+ response to NMDA was slightly enhanced by 0.1 mM LGG in normal (1.3 mM) Mg2+ medium, but in Mg(2+)-free medium LGG was stimulatory at low (0.1-1 microM) NMDA and inhibitory at high (0.1-1 mM) NMDA concentrations. In the absence of Mg2+, LGG alone increased cytosolic free Ca2+ and depolarized the cells. These effects were potentiated by glycine and blocked by extracellular Mg2+, 2-amino-5-phosphonopentanoate (APV), 7-chlorokynurenate, 3-amino-1-hydroxypyrrolidin-2-one (HA-966) and 5,7-dinitroquinoxaline-2,3-dione (MNQX). The results indicate that LGG is a partial NMDA agonist. On the other hand, the non-NMDA antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) also inhibited the effects of LGG. This indicates an involvement of non-NMDA receptors in the actions of LGG. The consequent depolarization may also contribute to the activation of NMDA receptor-governed ionophores.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Calcium; Cells, Cultured; Cerebellum; Dipeptides; Drug Synergism; Glutamates; Glutamic Acid; Glycine; Magnesium; N-Methylaspartate; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate