Leeson P D, Baker R, Carling R W, Curtis N R, Moore K W, Williams B J, Foster A C, Donald A E, Kemp J A, Marshall G R
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
J Med Chem. 1991 Apr;34(4):1243-52. doi: 10.1021/jm00108a002.
Derivatives of the nonselective excitatory amino acid antagonist kynurenic acid (4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1) have been synthesized and evaluated for in vitro antagonist activity at the excitatory amino acid receptors sensitive to N-methyl-D-aspartic acid (NMDA), quisqualic acid (QUIS or AMPA), and kainic acid (KA). Introduction of substituents at the 5-, 7-, and 5,7-positions resulted in analogues having selective NMDA antagonist action, as a result of blockade of the glycine modulatory (or coagonist) site on the NMDA receptor. Regression analysis suggested a requirement for optimally sized, hydrophobic 5- and 7-substituents, with bulk tolerance being greater at the 5-position. Optimization led to the 5-iodo-7-chloro derivative (53), which is the most potent and selective glycine/NMDA antagonist to date (IC50 vs [3H]glycine binding, 32 nM; IC50's for other excitatory amino acid receptor sites, greater than 100 microM). Substitution of 1 at the 6-position resulted in compounds having selective non-NMDA antagonism and 8-substituted compounds were inactive at all receptors. The retention of glycine/NMDA antagonist activity in heterocyclic ring modified analogues, such as the oxanilide 69 and the 2-carboxybenzimidazole 70, suggests that the 4-oxo tautomer of 1 and its derivatives is required for activity. Structurally related quinoxaline-2,3-diones are also glycine/NMDA antagonists, but are not selective and are less potent than the 1 derivatives, and additionally show different structure-activity requirements for aromatic ring substitution. On the basis of these results, a model accounting for glycine receptor binding of the 1 derived antagonists is proposed, comprising (a) size-limited, hydrophobic binding of the benzene ring, (b) hydrogen-bond acceptance by the 4-oxo group, (c) hydrogen-bond donation by the 1-amino group, and (d) a Coulombic attraction of the 2-carboxylate. The model can also account for the binding of quinoxaline-2,3-diones, quinoxalic acids, and 2-carboxybenzimidazoles.
非选择性兴奋性氨基酸拮抗剂犬尿喹啉酸（4-氧代-1,4-二氢喹啉-2-羧酸，1）的衍生物已被合成，并针对对N-甲基-D-天冬氨酸（NMDA）、quisqualic酸（QUIS或AMPA）和海人酸（KA）敏感的兴奋性氨基酸受体进行了体外拮抗剂活性评估。在5-、7-和5,7-位引入取代基后，得到了具有选择性NMDA拮抗剂作用的类似物，这是由于其阻断了NMDA受体上的甘氨酸调节（或共激动剂）位点。回归分析表明，需要5-和7-位具有最佳尺寸的疏水性取代基，且5-位对体积的耐受性更大。优化后得到了5-碘-7-氯衍生物（53），它是迄今为止最有效和选择性最高的甘氨酸/NMDA拮抗剂（对[3H]甘氨酸结合的IC50为32 nM；对其他兴奋性氨基酸受体位点的IC50大于100 μM）。在6-位取代1得到的化合物具有选择性非NMDA拮抗作用，而8-位取代的化合物在所有受体上均无活性。杂环修饰类似物如草酰苯胺69和2-羧基苯并咪唑70中甘氨酸/NMDA拮抗剂活性的保留表明，1及其衍生物的4-氧代互变异构体是活性所必需的。结构相关的喹喔啉-2,3-二酮也是甘氨酸/NMDA拮抗剂，但不具有选择性且效力低于1的衍生物，此外，它们对芳环取代显示出不同的构效关系要求。基于这些结果，提出了一个解释1衍生拮抗剂与甘氨酸受体结合的模型，该模型包括：（a）苯环的尺寸受限的疏水性结合；（b）4-氧代基团的氢键接受；（c）1-氨基的氢键供体；（d）2-羧酸盐的库仑吸引力。该模型也可以解释喹喔啉-2,3-二酮、喹喔啉酸和2-羧基苯并咪唑的结合。
