Graduate School of Science, Osaka University, Toyonaka, 560-0043, Japan.
RIKEN Center for Brain Research, Wako, Saitama, 351-0198, Japan.
Org Biomol Chem. 2020 Nov 7;18(41):8467-8473. doi: 10.1039/d0ob01756f. Epub 2020 Oct 16.
Rhodopsin-like G protein-coupled receptor (GPCR) GPR55 is attracting attention as a pharmaceutical target, because of its relationship with various physiological and pathological events. Although GPR55 was initially deorphanized as a cannabinoid receptor, lysophosphatidylinositol (LPI) is now widely perceived to be an endogenous ligand of GPR55. Recently, lysophosphatidyl-β-d-glucoside (LPGlc) has been found to act on GPR55 to repel dorsal root ganglion (DRG) neurons. In this study, we designed and synthesized various LPGlc analogues having the squaryldiamide group as potential agonists of GPR55. By the axon turning assay, several analogues exhibited similar activities to that of LPGlc. These results will provide valuable information for understanding the mode of action of LPGlc and its analogues and for the discovery of potent and selective antagonists or agonists of GPR55.
类视紫红质 G 蛋白偶联受体（GPCR）GPR55 作为一种药物靶点引起了人们的关注，因为它与各种生理和病理事件有关。尽管 GPR55 最初被去孤儿化为大麻素受体，但现在广泛认为溶血磷脂酰肌醇（LPI）是 GPR55 的内源性配体。最近，溶血磷脂酰-β-D-葡萄糖苷（LPGlc）被发现作用于 GPR55 以排斥背根神经节（DRG）神经元。在这项研究中，我们设计并合成了各种具有 squaryldiamide 基团的 LPGlc 类似物，作为 GPR55 的潜在激动剂。通过轴突转向测定，几种类似物表现出与 LPGlc 相似的活性。这些结果将为理解 LPGlc 及其类似物的作用模式以及发现 GPR55 的有效和选择性拮抗剂或激动剂提供有价值的信息。
