Conformationally constrained analogues of 2-arachidonoylglycerol
Conformationally constrained analogues of 2-arachidonoylglycerol
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DOI：
10.1016/j.bmcl.2007.07.064
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发表时间：
2007-11-01
影响因子：
2.7
通讯作者：
Makriyannis, Alexandros
中科院分区：
文献类型：
--
作者：
Vadivel, Subramanian K.;Vardarajan, Sundarararnan;Makriyannis, Alexandros
设计了2-花生四烯酰甘油（2-AG）的新型单环类似物，以探索这种内源性大麻素配体在关键大麻能蛋白上的药理学构象。所有1，2，3-环己烷三醇的2-花生四烯酸酯[meso-7（AM 5504），（）+/- 8（AM 5503），和ineso-9（AM 5505）]都是通过2，3-二羟基环己酮的区域选择性酰化，然后选择性还原而合成的。以（2S，3S）-2，3-二羟基环己酮和（2 R，3R）-2，3-二羟基环己酮为原料，通过酶法合成了光学活性异构体（+）-8（AM4434）和（-）-8（AM4435）。这些头基限制和构象限制的2-AG类似物以及1-酮前体作为内源性大麻素失活水解酶单酰基甘油脂酶（MGL）和脂肪酸酰胺水解酶（FAAH）的底物进行了评价，并测试了它们对CBI和CB 2大麻素受体的亲和力。这些配体之间观察到的生物化学差异可以帮助定义在上述内源性大麻素蛋白靶点中的每一个处2-AG活性的构象要求。(c)2007爱思唯尔有限公司保留所有权利。
Novel monocyclic analogues of 2-arachidonoylglycerol (2-AG) were designed in order to explore the pharillacophoric conformations of this endocannabinoid ligand at the key cannabinergic proteins. All 2-arachidonoyl esters of 1,2,3-cyclohexanetriol [meso-7 (AM5504), ()+/- 8 (AM5503), and ineso-9 (AM5505)] were synthesized by regioselective acylation of 2,3-dihydroxycyclohexanone followed by selective reductions. The optically active isomers (+)-8 (AM4434) and (-)-8 (AM4435) were synthesized from (2S,3S)- and (2R,3R)-2,3-dihydroxycyclohexanone, respectively, via a chernoenzymatic route. These head group constrained and conformationally restricted analogues of 2-AG as well as the 1-keto precursors were evaluated as substrates for the endocannabinoid deactivating hydrolytic enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), and also were tested for their affinities for CBI and CB2 cannabinoid receptors. The observed biochemical differences between these ligands can help define the conformational requirements for 2-AG activity at each of the above endocannabinoid protein targets. (c) 2007 Elsevier Ltd. All rights reserved.