Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
ACS Chem Neurosci. 2014 Jul 16;5(7):576-87. doi: 10.1021/cn500082p. Epub 2014 May 14.
GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to Gαi. 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no Gαq-mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity.
GPR88 是一种富含纹状体的孤儿 G 蛋白偶联受体 (GPCR)。基因缺失和基因表达研究表明，GPR88 在纹状体功能的调节中发挥重要作用，并与精神疾病有关。然而，由于缺乏内源性和合成配体，GPR88 的信号转导途径和受体功能在很大程度上仍然未知。在本文中，我们报告了 GPR88 激动剂 2-PCCA 及其纯非对映异构体的合成，并在瞬时和稳定表达 GPR88 的 HEK293 细胞中对其功能进行了表征。2-PCCA 在表达 GPR88 的细胞中以浓度依赖的方式抑制异丙肾上腺素刺激的 cAMP 积累，但在对照细胞中没有抑制作用，这表明观察到的 cAMP 抑制是通过 GPR88 介导的，并且 GPR88 与 Gαi 偶联。2-PCCA 不会诱导 GPR88 细胞中的钙动员，表明没有 Gαq 介导的反应。还进行了 2-PCCA 的构效关系 (SAR) 研究，以探索 GPR88 激动剂活性的关键结构特征。
