Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor - Structure-activity relationship of 2-arachidonoylglycerol ether-linked analogues, and related compounds
Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor - Structure-activity relationship of 2-arachidonoylglycerol ether-linked analogues, and related compounds
复制标题
DOI：
10.1074/jbc.274.5.2794
复制
发表时间：
1999-01-29
影响因子：
4.8
通讯作者：
Ishima, Y
中科院分区：
文献类型：
--
作者：
Sugiura, T;Kodaka, T;Ishima, Y
内源性拟大麻分子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 108 -15细胞内游离Ca 2+浓度快速、短暂增加。我们研究了24种相关化合物（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检查的最有效的化合物：其活性可从低至0.3 nM检测到，并且2-花生四烯酰甘油诱导的最大响应超过了其他化合物的响应。HU-210和CP 55940（强效大麻素受体激动剂）的活性也可从低至0.3 nM检测到，而由这些化合物诱导的最大反应与2-花生四烯酸甘油相比较低。还发现Anandamide在该测定系统中充当部分激动剂。我们证实游离花生四烯酸未能引起反应。此外，我们发现，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。我们还证实，用各种大麻素受体激动剂预处理细胞可消除2-花生四烯酸甘油诱导的反应，而用其他神经递质或神经调质预处理细胞则不影响反应。这些结果有力地表明，大麻素CB 1受体最初是2-花生四烯酸甘油受体，2-花生四烯酸甘油是大麻素CB 1受体的内在生理配体。
An endogenous cannabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca2+ concentrations in NG108-15 cells through a cannabinoid CB1 receptor-dependent mechanism. We examined the activities of 24 relevant compounds (2-arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2-arachidonoylglycerol is the most potent compound examined so far: its activity was detectable from as low as 0.3 nM, and the maximal response induced by 2-arachidonoylglycerol exceeded the responses by others. Activities of HU-210 and CP55940, potent cannabinoid receptor agonists, were also detectable from as low as 0.3 nM, whereas the maximal responses induced by these compounds were low compared with 2-arachidonoylglycerol, Anandamide was also found to act as a partial agonist in this assay system. We confirmed that free arachidonic acid failed to elicit a response. Furthermore, we found 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. We also confirmed that pretreating cells with various cannabinoid receptor agonists nullified the response induced by 2-arachidonoylglycerol, whereas pretreating cells with other neurotransmitters or neuromodulators did not affect the response. 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.