Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy.
J Med Chem. 2011 Dec 22;54(24):8278-88. doi: 10.1021/jm200529h. Epub 2011 Nov 16.
Since the discovery of the endocannabinoid system, evidence has been progressively accumulating to suggest that 2-arachidonoylglycerol (2-AG) rather than anandamide (AEA) is the endogenous ligand for both cannabinoid (CB) receptors. Moreover, other studies have shown that another lipid molecule, 2-arachidonyl-glycerol ether (2-AGE, noladin ether), which acts as a full agonist at cannabinoid receptors, might occur in tissues. Having previously designed a resorcinol-AEA hybrid model, in this paper we have explored the cannabinoid receptor binding properties, the CB1 functional activity, and the stability to plasma esterases of a novel series of compounds characterized by the conversion of the amide head into the glycerol-ester or glycerol-ether head, typical of 2-AG or the "putative" endocannabinoid 2-AGE, respectively. Glyceryl esters 39 and 41 displayed greater potency for CB1 (Ki in the nanomolar range) than for CB2 receptors plus the potential to be exploited as useful hits for the development of novel 2-AG mimetics.
自从内源性大麻素系统被发现以来，越来越多的证据表明，2-花生四烯酸甘油（2-AG）而不是花生四烯酸乙醇胺（AEA）是大麻素（CB）受体的内源性配体。此外，其他研究表明，另一种脂质分子，2-花生四烯酰基甘油醚（2-AGE，诺拉汀醚），作为大麻素受体的完全激动剂，可能存在于组织中。在之前设计了间苯二酚-AEA 杂合模型之后，在本文中，我们探索了一系列新型化合物的大麻素受体结合特性、CB1 功能活性以及对血浆酯酶的稳定性，这些化合物的特征是将酰胺头转化为甘油酯或甘油醚头，分别类似于 2-AG 或“假定”内源性大麻素 2-AGE。甘油酯 39 和 41 对 CB1 的活性（纳摩尔范围内的 Ki）大于对 CB2 受体的活性，并且有可能被开发为新型 2-AG 类似物的有用命中物。
