4-Amido-2-carboxytetrahydroquinolines. Structure-Activity Relationships for Antagonism at the Glycine Site of the NMDA Receptor

Article abstract of DOI:10.1021/jm00089a004

trans-2-Carboxy-5,7-dichloro-4-amidotetrahydroquinolines, evolved from the lead 5,7-dichlorokynurenic acid, have been synthesized and tested for in vitro antagonist activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor.Optimization of the 4-substituent has provided antagonists having nanomolar affinity, including the urea trans-2-carboxy-5,7-dichloro-4-<<(phenylamino)carbonyl>amino>-1,2,3,4-tetrahydroquinoline (35; IC50 = 7.4 nM vs <3H>glycine binding; K_b = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most poten t NMDA antagonists yet found.The absolute stereochemical requirements for binding were found to be 2S,4R, showing that, in common with other glycine-site NMDA receptor ligands, the unnatural configuration at the α-amino acid center is required.The preferred conformation of the trans-2,4-disubstituted tetrahydroquinoline system, as shown by X-ray crystallography and 1H NMR studies, places the 2-carboxyl pseudoequatorial and the 4-substituent pseudoaxial.Modifications of the 4-amide show that bulky substituents are tolerated and reveal the critical importance for activity of correct positioning of the carbonyl group.The high affinity of trans-2-carboxy-5,7-dichloro-4-<1-(3-phenyl-2-oxoimidazolidinyl)>-1,2,3,4-tetrahydroquinoline (55; IC50 = 6 nM) suggests that the Z,Z-conformer of the phenyl urea moiety in 35 is recognized by the receptor.Molecular modeling studies show that the 4-carbonyl groups of the kynurenic acids, the tetrahydroquinolines, and related antagonists based on N-(chlorophenyl)glycine, can interact with a single putative H-bond donor on the receptor.The results allow the establishment of a three-dimensional pharma cophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.