Resorcinol-sn-Glycerol Derivatives: Novel 2-Arachidonoylglycerol Mimetics Endowed with High Affinity and Selectivity for Cannabinoid Type 1 Receptor

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• 作者：Antonella Brizzi ; Maria Grazia Cascio ; Maria Frosini ; Alessia Ligresti ; Francesca Aiello ; Irene Biotti ; Vittorio Brizzi ; Roger Guy Pertwee ; Federico Corelli ; Vincenzo Di Marzo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8278-8288
• 全文大小：421K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

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鈥揂EA 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 鈥減utative鈥?endocannabinoid 2-AGE, respectively. Glyceryl esters 39 and 41 displayed greater potency for CB₁ (K_i 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.