Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist
Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist
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DOI：
10.1038/sj.bjp.0705792
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发表时间：
2004-06-01
影响因子：
7.3
通讯作者：
Mackie, K
中科院分区：
文献类型：
--
作者：
Luk, T;Jin, WZ;Mackie, K
1激动剂功效与G蛋白偶联受体信号传导脱敏速率的关系是有争议的。2在非洲爪蟾卵母细胞中表达内向整流钾通道（GIRK），我们设计了一种信号传导测定，其清楚地鉴定具有低内在功效的CBI大麻素受体激动剂。3在该测定中，合成的CBI激动剂，AM 411、AM 782、AM 1902、AM 2233和WIN 55，212-2和内源性大麻素2-花生四烯酸酯是完全激动剂。4合成的CB 1激动剂AM356（甲基大麻素）、内源性大麻素anandamide和2-花生四烯酸醚以及植物大麻素Delta（9）THC是部分激动剂。5 CBI的脱敏率与激动剂效力无关。WIN 55、212-2、AM 782、AM 1902、AM 2233和2-花生四烯酸甘油酯均快速脱敏，脱敏率从14%min（-1）到10%min（-1）不等。AM356、AM411、大麻素和Delta（9）THC都以5%min（~ 100%）的速率相当慢地脱敏。6尽管具有高效力和功效，但AM411与大麻素和Delta（9）THC一样慢地脱敏。7 CB 1激动剂功效和脱敏速率不一定相关。
1 The relationship of agonist efficacy to the rate of G protein-coupled receptor signaling desensitization is controversial.2 Expressing inwardly rectifying potassium channels (GIRKs) in Xenopus oocytes, we have devised a signaling assay that clearly identifies CBI cannabinoid receptor agonists with low intrinsic efficacy.3 In this assay, the synthetic CBI agonists, AM411, AM782, AM1902, AM2233 and WIN55,212-2 and the endogenous cannabinoid, 2-arachidonoyl ester, were full agonists.4 The synthetic CB1 agonist AM356 (methanandamide), the endogenous cannabinoids, anandamide and 2-acachidonoyl ether, and the phytocannabinoid, Delta(9)THC, were partial agonists.5 The rate of desensitization of CBI was independent of agonist efficacy. WIN55,212-2, AM782, AM1902, AM2233, and 2-arachidonoyl glycerol ester all desensitized quickly, with desensitization rates varying from 14% min(-1) to 10% min(-1). AM356, AM411, anandamide, and Delta(9)THC all desensitized considerably slower, at a rate of 5% min(-1).6 Despite high potency and efficacy, AM411 desensitized as slowly as anandamide and Delta(9)THC.7 CB1 agonist efficacy and rate of desensitization are not necessarily related.