Schoepp D D, Johnson B G, Salhoff C R, Valli M J, Desai M A, Burnett J P, Mayne N G, Monn J A
Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
Neuropharmacology. 1995 Aug;34(8):843-50. doi: 10.1016/0028-3908(95)00061-a.
Metabotropic glutamate receptors (mGluRs) are a heterogeneous family of G-protein coupled receptors that are linked to multiple second messengers in the rat hippocampus. The compound 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) has been widely used to activate this class of receptors and study their functions in situ. However, 1S,3R-ACPD acts on multiple mGluR subtypes to produce multiple alterations in second messengers. We report here that the aza-substituted analog of 1S,3R-ACPD, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), is a highly selective agonist for negatively-coupled cAMP-linked mGluRs in the rat hippocampus, with similar potency in mGluR2 expressing cells. 1S,3R-ACPD decreases forskolin-stimulated cAMP formation, increases basal cAMP formation, and increases phosphoinositide hydrolysis in the rat hippocampus. However, 2R,4R-APDC inhibited forskolin-stimulated cAMP, but had none of the other activities of 1S,3R-ACPD. Furthermore, 2R,4R-APDC had no measurable ionotropic glutamate receptor affinity in rat hippocampus, as indicated by lack of effects on basal and glutamate agonist-evoked [3H]norepinephrine release. 2R,4R-APDC also inhibited forskolin-stimulated cAMP formation in human mGluR2 expressing cells with about three-fold greater potency than 1S,3R-ACPD, but unlike 1S,3R-ACPD, showed no appreciable activation of phosphoinostide hydrolysis in human mGluR1 alpha expressing cells. Thus, 2R,4R-APDC should be a useful pharmacological agent to explore the functions of mGluRs coupled to inhibition of adenylate cyclase.
代谢型谷氨酸受体（mGluRs）是一类异质性的G蛋白偶联受体家族，在大鼠海马体中与多种第二信使相连。化合物1S,3R-1-氨基环戊烷-1,3-二羧酸（1S,3R-ACPD）已被广泛用于激活这类受体并原位研究其功能。然而，1S,3R-ACPD作用于多种mGluR亚型，会在第二信使中产生多种变化。我们在此报告，1S,3R-ACPD的氮杂取代类似物2R,4R-4-氨基吡咯烷-2,4-二羧酸（2R,4R-APDC）是大鼠海马体中负偶联cAMP相关mGluRs的高度选择性激动剂，在表达mGluR2的细胞中具有相似的效力。1S,3R-ACPD可降低福斯高林刺激的cAMP生成，增加基础cAMP生成，并增加大鼠海马体中的磷酸肌醇水解。然而，2R,4R-APDC抑制了福斯高林刺激的cAMP生成，但没有1S,3R-ACPD的其他活性。此外，如对基础和谷氨酸激动剂诱发的[3H]去甲肾上腺素释放无影响所示，2R,4R-APDC在大鼠海马体中没有可测量的离子型谷氨酸受体亲和力。2R,4R-APDC在表达人mGluR2的细胞中也抑制福斯高林刺激的cAMP生成，效力比1S,3R-ACPD高约三倍，但与1S,3R-ACPD不同，在表达人mGluR1α的细胞中未显示出明显的磷酸肌醇水解激活。因此，2R,4R-APDC应该是一种有用的药理学试剂，可用于探索与抑制腺苷酸环化酶偶联的mGluRs的功能。
