2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist

一种内源性的类大麻素分子，2-花生四烯醇甘油，通过大麻素CB1受体依赖机制，诱导ng108 -15细胞内游离Ca^<2+>浓度的快速、短暂增加。我们检查了一些相关化合物（2-花生四烯醇甘油，其结构类似物和几种合成大麻素）的活性。我们发现2-花生四烯醇甘油是迄今为止检测到的最有效的化合物。我们证实了代谢稳定的2-花生四烯醇甘油醚连接类似物具有明显的激动活性，尽管其活性明显低于2-花生四烯醇甘油。这些结果强烈提示大麻素CB1受体最初是一个2-花生四烯醇甘油受体，2-花生四烯醇甘油是大麻素CB1受体的内在生理配体。接下来，我们通过反相高效液相色谱和气相色谱-质谱分析检测了从不同鼠组织中获得的单甘油三酯的分子种类组成。我们证实，内源性大麻素受体激动剂2-花生四烯醇甘油是大脑中最丰富的单酰基甘油分子之一。在肝脏、脾脏、肺和肾脏中也发现了大量的2-花生四烯醇甘油。我们还发现人内皮细胞在受凝血酶刺激时产生2-花生四烯醇甘油。我们证实了人类血管平滑肌细胞具有大麻素CB1受体mRNA。因此，内源性大麻素受体激动剂2-花生四烯醇甘油可能是一种血管调节剂。

An endogenous carmabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca^<2+> concentrations in NG1O8-15 cells through a cannabinoid CB1 receptor-dependent mechanism. We examined the activities of a number of relevant compounds (2-arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2-arachidonoylglycerol is the most potent compound examined so far. We confirmed that a metabolically stable ether-linked analogue of 2-arachidonoylglycerol possesses appreciable agonistic activity, although its activity was apparently lower than that of 2-arachidonoylglycerol. These results strongly suggested that the cannabinoid CB1 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic physiological ligand for the cannabinoid CB1 receptor.Next we examined the molecular species compositions of monoacyiglycerols obtained from various rattissues by reverse-phase HPLC and GC-MS analyses. We confirmed that 2-arachidonoylglycerol, an endogenous cannabinoid receptor agonist, is one of most abundant molecular species of monoacylglycerols in the brain. Substantial amounts of 2-arachidonoylglycerol were also found in liver, spleen, lung and kidney. We also found that human endothelial cells produce 2-arachidonoylglycerol when stimulated with thrombin. We confirmed that human vascular smooth muscle cells possesses the cannabinoid CB1 receptor mRNA.It is possible, therefore, that 2-arachidonoylglycerol, an endogenous cannabinoid receptor agonist, is a possible vasomodulator.