Jaen J C, Laborde E, Bucsh R A, Caprathe B W, Sorenson R J, Fergus J, Spiegel K, Marks J, Dickerson M R, Davis R E
Department of Chemistry, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J Med Chem. 1995 Oct 27;38(22):4439-45. doi: 10.1021/jm00022a008.
The ability of a series of substituted kynurenic acids, thienopyridinonecarboxylic acids, and related compounds to inhibit the binding of nerve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated in a radioligand binding assay that utilized a biotinylated derivative of the extracellular domain of p75 NGFR (p75ext) fixed to streptavidin-coated plastic wells. Two compounds, 6-aminokynurenic acid (5h) and the 3-methyl ester of 4,7-dihydro-2-methyl-7-oxothieno[3,2-b]pyridine-3,5-dicarboxylic acid (16), were found to inhibit the binding of [125I]NGF to p75ext with IC50 values in the low micromolar range. Other amino-substituted kynurenic acids also possessed activity at slightly higher concentrations. Several structural features seem to be essential, including the carboxylic acid, a polar group on the benzene ring (or thiophene ring, in the case of analogues of 16), and the C-4 carbonyl group in the pyridinone ring. These compounds were also found to inhibit the binding of [125I]NGF to its receptors in membranes from PC12 cells (which express p75 as well as trka receptors for NGF) and DG44-CHO cells (transfected with full length p75 NGFR). The available data for 5h and 16 do not allow the determination of whether the effects of these compounds are mediated by their interaction with NGF or the NGF receptors.
在一项放射性配体结合试验中，评估了一系列取代犬尿氨酸、噻吩并吡啶酮羧酸及相关化合物抑制神经生长因子（NGF）与p75 NGF受体（NGFR）结合的能力。该试验使用固定在链霉亲和素包被塑料孔上的p75 NGFR细胞外结构域（p75ext）的生物素化衍生物。发现两种化合物，即6-氨基犬尿氨酸（5h）和4,7-二氢-2-甲基-7-氧代噻吩并[3,2-b]吡啶-3,5-二羧酸的3-甲酯（16），能够抑制[125I]NGF与p75ext的结合，IC50值处于低微摩尔范围。其他氨基取代的犬尿氨酸在稍高浓度下也具有活性。几个结构特征似乎至关重要，包括羧酸、苯环（对于16的类似物则为噻吩环）上的极性基团以及吡啶酮环中的C-4羰基。还发现这些化合物能够抑制[125I]NGF与PC12细胞（表达p75以及NGF的trka受体）和DG44-CHO细胞（转染全长p75 NGFR）膜上受体的结合。关于5h和16的现有数据无法确定这些化合物的作用是否通过它们与NGF或NGF受体的相互作用介导。
