Cavanni P, Pinnola V, Mugnaini M, Trist D, Van Amsterdam F T, Ferraguti F
Department of Pharmacology, Glaxo Research Laboratories, Verona, Italy.
Eur J Pharmacol. 1994 Sep 15;269(1):9-15. doi: 10.1016/0922-4106(94)90020-5.
Three carboxyphenylglycine derivatives were examined for their activity on glutamate metabotropic receptors negatively linked to adenylate cyclase. Chinese hamster ovary cells stably expressing mGlu2 and mGlu4 were utilised for this study. A receptor binding analysis was also performed for the main classes of glutamate ionotropic receptors and for the glycine binding site on the NMDA-receptor complex. In mGlu2 expressing cells (S)4-carboxy-3-hydroxyphenylglycine and (S)4-carboxy-phenylglycine antagonized forskolin-stimulated cAMP levels, with EC50 of 21 and 970 microM, respectively, acting as agonists at this receptor subtype, whereas (RS) alpha-methyl-4-carboxyphenylglycine antagonized glutamate response in these cells. None of these compounds showed any agonistic or antagonistic activity on mGlu4 expressing cells. No affinity for the ionotropic receptors (NMDA, AMPA and kainate) and for the glycine site of the NMDA-receptor complex was found using the receptor binding approach, except for (RS)4-carboxy-3-hydroxyphenylglycine which showed a pKi of 5.68 in ((+/-)2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding for NMDA receptor, although this can be ascribed to the (R) form of the racemic mixture.
研究了三种羧基苯基甘氨酸衍生物对与腺苷酸环化酶负相关的谷氨酸代谢型受体的活性。本研究使用稳定表达mGlu2和mGlu4的中国仓鼠卵巢细胞。还对主要类型的谷氨酸离子型受体以及NMDA受体复合物上的甘氨酸结合位点进行了受体结合分析。在表达mGlu2的细胞中，(S)-4-羧基-3-羟基苯基甘氨酸和(S)-4-羧基苯基甘氨酸拮抗福斯可林刺激的cAMP水平，EC50分别为21和970μM，在该受体亚型上作为激动剂起作用，而(RS)-α-甲基-4-羧基苯基甘氨酸拮抗这些细胞中的谷氨酸反应。这些化合物在表达mGlu4的细胞中均未显示出任何激动或拮抗活性。使用受体结合方法，未发现对离子型受体（NMDA、AMPA和海人藻酸）以及NMDA受体复合物的甘氨酸位点有亲和力，除了(RS)-4-羧基-3-羟基苯基甘氨酸在((±)-2-羧基哌嗪-4-基)丙基-1-膦酸与NMDA受体结合时显示出pKi为5.68，尽管这可归因于外消旋混合物的(R)形式。
