Thieno[2,3-b)pyridinones as Antagonists on the Glycine Site of the N-methyl-ᴅ-aspartate Receptor - Binding Studies, Molecular Modeling and structure-Activity-Relationships ^†

Within the frame of the synthesis of glycine antagonists, a series of novel thieno[2,3- b]pyridinones with substituted phenyl residues in position 5 were synthesised to investigate the importance of the torsion angle between the pyridinone skeleton and the phenyl ring for binding affinity. The parent compound, 4-hydroxy-5-phenylthieno[2,3-b]pyridine-6(7H)-one, and its thienyl analogue, exhibited highest potencies, whereas compounds with ortho-substituted aryl moieties in position 5 showed decreased activities. This seems to be due to unfavourable steric interactions and increased torsion angles between the thieno[2,3- b]pyridinone system and the aryl substituent in position 5. Further evidence is drawn by QSAR studies, which showed an inverse relationship between the size of the ortho-substituent and the binding affinity.