2-Carboxytetrahydroquinolines. Conformational and stereochemical requirements for antagonism of the glycine site on the NMDA receptor.
2-Carboxy-1,2,3,4-tetrahydroquinoline derivatives, derived from kynurenic acid, have been synthesized and evaluated for in vitro antagonist activity at the glycine site on the NMDA receptor. 2,3-Dihydrokynurenic acids show reduced potency relative to the parent lead compounds (Table I) possibly as a result of conformational effects. Removal of the 4-oxo group results in further reduced potency, but introduction of a cis-carboxymethyl group to the 4-position restores antagonist activity (Tables III and IV). Replacement of the keto group of 5,7-dichloro-2,3-dihydrokynurenic acid with other alternative H-bonding groups, for example cis- and trans-benzyloxycarbonyl and cis- and trans-carboxamido (Table V), gives comparable activity, but there is negligible stereoselectivity. A significant increase in potency and stereoselectivity is seen within the 4-acetate series (Table VI). The trans-4-acetic acid is significantly more potent than the corresponding lead kynurenic acid and has 100-fold greater affinity than the cis isomer. The results are consistent with a requirement in binding for a pseudoequatorially placed 2-carboxylate and clearly demonstrate the importance for binding of a correctly positioned hydrogen-bond-accepting group at the 4-position. The high-affinity binding of an anionic group in the 4-substituent binding pocket suggests that the glycine site and the neurotransmitter recognition (NMDA) site may have some features in common.
Carling
R W
RW
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK.
Leeson
P D
PD
Moseley
A M
AM
Baker
R
R
Foster
A C
AC
Grimwood
S
S
Kemp
J A
JA
Marshall
G R
GR
D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005998:Glycine / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007736:Kynurenic Acid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D011804:Quinolines; D016194:Receptors, N-Methyl-D-Aspartate; C074907:2-carboxy-4-(carboxymethyl)-5,7-dichloro-1,2,3,4-tetrahydroquinoline; D007736:Kynurenic Acid; D005998:Glycine