Hydrogen-Bond Patterns in l,4-Dihydror2,3-quinoxalinediones: Ligands for the Glycine Modulatory Site on the NMDA Receptor

摘要

The crystal structures of five l,4-dihydro-2,3-quinoxali-nediones, antagonists of the NMDA modulatory glycine binding site on the excitary amino acid (EAA) receptor complex, have been determined: (I) 6,7-dinitro-l,4-dihydro-2,3-quinoxalinedione (DNQX); (II) 5,7-dinitro-l,4-dihydro-2,3-quinoxalinedione (MNQX); (III) 6-nitro-l,4-dihydro-2,3-quinoxalinedione hydrate; (IV) 6,7-di-chloro-l,4-dihydro-2,3-quinoxalinedione; (V) 5,7-di-chloro-1,4-dihydro-2,3-quinoxalinedione dimethylform-amide. The crystal structure of the most active compound (II) contains a unique intramolecular N-H' o -O(N02) 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), (HI) and (IV) head-to-tail 7r-stacking is found between molecules connected by a center of symmetry. The geometries of the hydrogen-bonded -NH-C=O fragments show evidence of jr-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.