Milman Garry, Maor Yehoshua, Abu-Lafi Saleh, Horowitz Michal, Gallily Ruth, Batkai Sandor, Mo Fong-Ming, Offertaler Laszlo, Pacher Pal, Kunos George, Mechoulam Raphael
Department of Medicinal Chemistry and Natural Products, Medical Faculty, and Laboratory of Environmental Physiology, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2428-33. doi: 10.1073/pnas.0510676103. Epub 2006 Feb 7.
The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.
内源性大麻素N-花生四烯酸乙醇胺（花生四烯酸乙醇胺）在中枢神经系统和外周均有发现，在众多生理系统中发挥作用。人们可能会认为，化学相关的N-花生四烯酰-L-丝氨酸（ARA-S）也可能与花生四烯酸乙醇胺一起形成。我们现已从牛脑中分离出ARA-S，并通过与合成的ARA-S进行比较来阐明其结构。与花生四烯酸乙醇胺相反，ARA-S与大麻素CB1和CB2或香草酸TRPV1（瞬时受体电位香草酸1）受体的结合非常弱。然而，它可引起大鼠离体肠系膜动脉和腹主动脉的内皮依赖性血管舒张，并刺激培养的内皮细胞中p44/42丝裂原活化蛋白（MAP）激酶和蛋白激酶B/Akt的磷酸化。ARA-S还可抑制小鼠巨噬细胞系、野生型小鼠以及CB1或CB2受体缺陷小鼠中脂多糖诱导的肿瘤坏死因子-α的形成。这些作用中的许多与报道的异常大麻二酚（Abn-CBD）的作用相似，Abn-CBD是一种假定的新型大麻素型受体的合成激动剂。因此，ARA-S可能代表该受体的内源性激动剂。
