2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist

内源性拟大麻素分子2-花生四烯酸甘油通过大麻素CB 1受体依赖性机制诱导NG 10 8 -15细胞内游离Ca^2+浓度快速、短暂增加。我们研究了一些相关化合物（2-花生四烯酰甘油，其结构类似物和几种合成大麻素）的活性。我们发现，2-花生四烯酰甘油是迄今为止最有效的化合物。我们证实，代谢稳定的醚连接的类似物2-arachidonoylglycerol具有明显的激动活性，虽然它的活性明显低于2-arachidonoylglycerol。这些结果表明，大麻素CB 1受体最初是一种2-花生四烯酰甘油受体，而2-花生四烯酰甘油是大麻素CB 1受体的内在生理配体。我们证实了内源性大麻素受体激动剂2-花生四烯酰甘油是大脑中最丰富的单酰基甘油分子种类之一。在肝、脾、肺和肾中也发现了大量的2-花生四烯酰甘油。我们还发现，人内皮细胞产生2-花生四烯酸甘油时，凝血酶刺激。我们证实人血管平滑肌细胞中存在大麻素CB 1受体mRNA，因此，内源性大麻素受体激动剂2-花生四烯酸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.