Carling R W, Leeson P D, Moseley A M, Baker R, Foster A C, Grimwood S, Kemp J A, Marshall G R
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK.
J Med Chem. 1992 May 29;35(11):1942-53. doi: 10.1021/jm00089a003.
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.
源自犬尿喹啉酸的2-羧基-1,2,3,4-四氢喹啉衍生物已被合成，并对其在NMDA受体甘氨酸位点的体外拮抗活性进行了评估。与母体先导化合物相比，2,3-二氢犬尿喹啉酸的效力降低（表I），这可能是构象效应的结果。去除4-氧代基团会导致效力进一步降低，但在4位引入顺式羧甲基基团可恢复拮抗活性（表III和IV）。用其他替代氢键基团取代5,7-二氯-2,3-二氢犬尿喹啉酸的酮基，例如顺式和反式苄氧羰基以及顺式和反式羧酰胺（表V），可得到相当的活性，但立体选择性可忽略不计。在4-乙酸酯系列中观察到效力和立体选择性显著增加（表VI）。反式-4-乙酸的效力明显高于相应的先导犬尿喹啉酸，其亲和力比顺式异构体高100倍。结果与结合时对假赤道位置的2-羧酸盐的要求一致，并清楚地证明了在4位正确定位的氢键接受基团对结合的重要性。4-取代基结合口袋中阴离子基团的高亲和力结合表明，甘氨酸位点和神经递质识别（NMDA）位点可能有一些共同特征。
