Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand

内源性大麻素受体配体 2-花生四烯酰甘油的生理作用

• 批准号: 11672185
• 负责人: SUGIURA Takayuki
• 金额: $ 2.3万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672185/
• 关键词: 2-Arachidonoylglyarol; Ananolamide; Cannabinoid; Arachidonic acid; Marijuana; マリファナ; アラキドノイルグリセロール; モノグリセリド

We found that 2-arachidonoylglycerol (2-AG) induces rapid transient increases in intracellular free Ca^<2+> concentrations in HL-60 cells which express the cannabinoid CB2 receptor. We then examined the structure-activity relationship of 2-AG and other cannabinoid receptor ligands in detail. We found that an ether-linked analogue of 2-AG possesses significant biological activity, indicating that the structure of 2-AG itself, but not its metabolite, is actually recognized by the CB2 receptor molecule. Noticeably, the activities of ether-linked analogues and amide bond-containing analogues of 2-AG were considerably lower than that of 2-AG, suggesting that the presence of an ester linkage is crucially important for exhibiting strong agonistic activity. In contrast to 2-AG, anandamide was found to act as a weak partial agonist toward the CB2 receptor. The activity of Δ^9-tetrahydrocannabinol, at major constituent of marijuana, was also low. We further examined the activities of various 2-A … More G analogues and classical and synthetic cannabinoids. The activities of monoacylglycerols containing various saturated, monoenoic and dienoic fatty acids were very low. 2-AG acted as one of the most potent agonists toward the CB2 receptor. We concluded the CB2 receptor is originally a 2-AG receptor, and that Δ^9-tetrahydrocannabinol may interfere with the actions of 2-AG thereby eliciting various pharmacological effects. We then examined the level of 2-AG in the brain. Rat brain was found to contain 0.23 nmol/g tissue of 2-AG.We found that the level of 2-AG was elevated markedly in picrotoxinin-administered rat brain and in post-decapitative ischemic rat brain. We also found that a large amount of 2-AG was generated when brain homogenate was incubated in the presence of Ca^<2+>. We confirmed that 2-AG can be generated from inositol phospholipids through the action of phospholipase C and subsequent diacylglycerol lipase activity ; it seems very likely that the function of the cannabinoid receptors are closely related to increased inositol phospholipid metabolism. 2-AG rapidly generated in the brain after stimulation mat play important physiological roles in the regulation of neurotransmission. Less

我们发现，2-花生四烯酸甘油（2-AG）诱导表达大麻素CB 2受体的HL-60细胞内游离Ca^2+浓度的快速瞬时增加。然后，我们详细研究了2-AG和其他大麻素受体配体的结构-活性关系。我们发现2-AG的醚连接类似物具有显著的生物活性，表明2-AG本身的结构，而不是其代谢产物，实际上被CB 2受体分子识别。值得注意的是，2-AG的醚连接的类似物和含酰胺键的类似物的活性显著低于2-AG的活性，这表明酯键的存在对于表现出强激动活性至关重要。与2-AG相反，花生四烯酸被发现作为一个弱的部分激动剂对CB 2受体。大麻的主要成分Δ^9-四氢大麻酚的活性也很低。我们进一步检查了各种2-A的活动 ...更多信息 G类似物以及经典和合成大麻素。含有各种饱和脂肪酸、单烯脂肪酸和二烯脂肪酸的单酰基甘油的活性很低。2-AG是CB 2受体最有效的激动剂之一。我们得出结论，CB 2受体最初是2-AG受体，并且Δ^9-四氢大麻酚可能干扰2-AG的作用，从而引发各种药理学作用。然后我们检测了大脑中2-AG的水平。大鼠脑组织中2-AG含量为0.23nmol/g组织，印防己毒素组和断头缺血组脑组织中2-AG含量明显升高。我们还发现，当脑匀浆在Ca^<2+>存在下孵育时，产生大量的2-AG。我们证实，2-AG可以通过磷脂酶C和随后的二酰基甘油脂肪酶活性的作用从肌醇磷脂中产生;大麻素受体的功能似乎很可能与肌醇磷脂代谢增加密切相关。2-AG在刺激后迅速在脑内产生，在神经传递的调节中起着重要的生理作用。少

项目成果

Jorai,Z. et al.: "Cardiovascular effects of 2--arachidonoylglycerol"Hypertension. 35. 679-684 (2000)

乔莱，Z.

Takayuki Sugiura: "Evidence that the Cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor"J.Biol.Chem.. 274. 2794-2801 (1999)

Takayuki Sugiura：“大麻素 CB1 受体是 2-花生四烯酰甘油受体的证据”J.Biol.Chem.. 274. 2794-2801 (1999)

Sugiura, T.and Waku, K.: "2-Arachidonoylglycerol and the cannabinoid receptors (Review)"Chem.Phys.Lipids. 108. 89-106 (2000)

Sugiura, T. 和 Waku, K.：“2-花生四烯酰甘油和大麻素受体（评论）”Chem.Phys.Lipids。

Sugiura,T. & Waleu,K.: "2-Arachidonoylglycerol and the cannabinoid receptor"Chem.Phys.Lipids. 108. 89-106 (2000)

杉浦，T.

Suhara,Y. et al.: "Synthesis and biological activities of 2-arachidonoylglycerol and its analogues"Chem.Pharm.Bull.. 48. 903-907 (2000)

苏原，Y.