(<i>R</i>)‑<i>N</i>‑(1-Methyl-2-hydroxyethyl)-13‑(<i>S</i>)‑methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes

The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13S,1′R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor (Ki of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 ± 0.2 nM). (13S,1′R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356. This novel analogue will serve as a very useful endocannabinoid probe.合成强效且代谢稳定的内源性大麻素（endocannabinoids）极具挑战性。本研究报道一种手性花生四烯酸乙醇胺（AEA）类似物——(13S,1′R)-二甲基安andamide（AMG315，3a），其作为CB1受体的高亲和力配体，抑制常数（Ki）为7.8±1.4 nM，且在体外实验中表现为强效CB1受体激动剂，半最大效应浓度（EC50）为0.6±0.2 nM。(13S,1′R)-二甲基安andamide是首款针对所有内源性大麻素水解酶以及氧化酶环氧合酶-2（COX-2）均具备显著稳定性的强效AEA类似物。在采用完全弗氏佐剂（CFA）诱导的炎性疼痛模型开展的体内实验中，3a的镇痛效果优于内源性AEA及其水解稳定类似物AM356。这款新型类似物将成为极具应用价值的内源性大麻素研究探针。