Leeson P D, Carling R W, Moore K W, Moseley A M, Smith J D, Stevenson G, Chan T, Baker R, Foster A C, Grimwood S
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Harlow, Essex.
J Med Chem. 1992 May 29;35(11):1954-68. 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; 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.
从先导化合物5,7-二氯犬尿喹啉酸衍生而来的反式-2-羧基-5,7-二氯-4-氨基四氢喹啉已被合成，并测试了其在N-甲基-D-天冬氨酸（NMDA）受体甘氨酸位点的体外拮抗活性。对4-取代基的优化得到了具有纳摩尔亲和力的拮抗剂，包括脲反式-2-羧基-5,7-二氯-4[[(苯基氨基)羰基]氨基]-1,2,3,4-四氢喹啉（35；与[3H]甘氨酸结合的IC50 = 7.4 nM；在大鼠皮层切片中阻断NMDA反应的Kb = 130 nM），它是迄今发现的最有效的NMDA拮抗剂之一。发现结合的绝对立体化学要求为2S,4R，这表明与其他甘氨酸位点NMDA受体配体一样，α-氨基酸中心需要非天然构型。如X射线晶体学和1H NMR研究所示，反式-2,4-二取代四氢喹啉系统的优选构象使2-羧基处于假赤道位置，4-取代基处于假轴向位置。对4-酰胺的修饰表明，大体积取代基是可耐受的，并揭示了羰基正确定位对活性的关键重要性。反式-2-羧基-5,7-二氯-4-[1-(3-苯基-2-氧代咪唑烷基)]-1,2,3,4-四氢喹啉（55；IC50 = 6 nM）的高亲和力表明受体识别35中苯基脲部分的Z,Z构象体。分子模拟研究表明，犬尿喹啉酸、四氢喹啉以及基于N-(氯苯基)甘氨酸的相关拮抗剂的4-羰基可与受体上单个假定的氢键供体相互作用。这些结果有助于建立甘氨酸受体拮抗剂位点的三维药效团，其中包含一个新定义的体积耐受性/疏水区。
