Synthetic Cellular Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Chem Commun (Camb). 2018 Jul 26;54(61):8470-8473. doi: 10.1039/c8cc04467h.
Lysophosphatidyl glucoside (LPGlc) is a structurally unique glycolipid that acts as a guidance cue for extending axons during central nervous system development by activating the class A G protein coupled receptor (GPR) 55 of spinal cord sensory axons. GPR55 not only plays an important role during development, but is also implicated in many disease states, rendering molecules that target GPR55 of widespread interest. In this study, we developed synthetic access to a novel class of LPGlc analogues featuring a squaryl diamide group as surrogate for the phosphodiester. We report the facile synthesis of a series of LPGlc analogues, their GPR dependent biological activity and a systematic analysis of the structure-activity relationship in regards to GPR55 modulation. The lead compound featuring identical configuration at all stereocenters compared to natural LPGlc exhibits an activity to repel axons of dorsal root ganglion (DGR) nociceptive neurons.
溶血磷脂酰葡萄糖苷（LPGlc）是一种结构独特的糖脂，它通过激活脊髓感觉轴突的 A 类 G 蛋白偶联受体（GPR）55，作为中枢神经系统发育过程中延伸轴突的导向线索。GPR55 不仅在发育过程中发挥重要作用，而且还与许多疾病状态有关，这使得靶向 GPR55 的分子成为广泛关注的对象。在这项研究中，我们开发了一种新型 LPGlc 类似物的合成方法，其中含有一个 Squaryl 二酰胺基团作为磷酸二酯的替代物。我们报告了一系列 LPGlc 类似物的简便合成方法、它们的 GPR 依赖性生物学活性以及对 GPR55 调节的结构-活性关系的系统分析。与天然 LPGlc 相比，具有相同构型的所有立体中心的先导化合物表现出排斥背根神经节（DGR）伤害感受神经元轴突的活性。
