4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor

Abstract

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; Kb = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most potent 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 alpha-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 pharmacophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.

A Novel Series of 2-Carboxytetrahydroquinolines Provides New Insights into the Eastern Region of Glycine Site NMDA Antagonists

“…Compounds 9, 10, and 12 in the amide series confirm the general findings of Leeson et al [3] , describing the trans-isomers of 4-substituted 2-carboxytetrahydroquinolines as more active than the corresponding cis-isomers. This effect of stereoselectivity on affinity could be also observed in patch clamp recordings throughout the amide series ( Table 1).…”

“…The ester group was then saponified with LiOH in THF or, when epimerization into the trans-isomers was required, reacted with sodium methoxide [3] . Activation of the primary amino function with N,N′-carbonyldiimidazole (CDI) followed by the addition of the amine linker yielded the urea derivatives.…”

Synthesis and evaluation of 5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐[18F]fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid as a potential NMDA ligand to study glutamatergic neurotransmission in vivo

“…9 The [ 18 F]fluorine labelled derivative trans-5,7-dichloro-4-(3-{4- [4-(2-[ 18 F]fluoroethyl)-piperazin-1-yl]-phenyl}-ureido)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (2) of the lead structure 1 was considered for in vivo visualisation of the NMDA receptor. In the following figures and schemes the 2R,4S-configuration represents the trans-isomers, whilst the 2S,4S-configuration represents the cis-isomers (Figure1).…”

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropane-carboxamide (PPDC), a New Class of NMDA-Receptor Antagonist: Molecular Design by a Novel Conformational Restriction Strategy

“…However, their preclinical studies suggest that brain penetration is usually insufficient. Consequently, antagonists with improved brain penetration are now being developed (16,17). Considering these results, another type of efficient NMDAreceptor antagonist is eagerly desired.…”