The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 NorthTorrey Pines Road, La Jolla, California 92037, United States.
ACS Chem Neurosci. 2012 May 16;3(5):418-26. doi: 10.1021/cn200089j. Epub 2011 Oct 10.
The two major endocannabinoid transmitters, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are degraded by distinct enzymes in the nervous system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. FAAH and MAGL inhibitors cause elevations in brain AEA and 2-AG levels, respectively, and reduce pain, anxiety, and depression in rodents without causing the full spectrum of psychotropic behavioral effects observed with direct cannabinoid receptor-1 (CB1) agonists. These findings have inspired the development of several classes of endocannabinoid hydrolase inhibitors, most of which have been optimized to show specificity for either FAAH or MAGL or, in certain cases, equipotent activity for both enzymes. Here, we investigate an unusual class of O-hydroxyacetamide carbamate inhibitors and find that individual compounds from this class can serve as selective FAAH or dual FAAH/MAGL inhibitors in vivo across a dose range (0.125-12.5 mg kg(-1)) suitable for behavioral studies. Competitive and click chemistry activity-based protein profiling confirmed that the O-hydroxyacetamide carbamate SA-57 is remarkably selective for FAAH and MAGL in vivo, targeting only one other enzyme in brain, the additional 2-AG hydrolase ABHD6. These data designate O-hydroxyacetamide carbamates as a versatile chemotype for creating endocannabinoid hydrolase inhibitors that display excellent in vivo activity and tunable selectivity for FAAH-anandamide versus MAGL (and ABHD6)-2-AG pathways.
两种主要的内源性大麻素递质，花生四烯酸乙醇胺（AEA）和 2-花生四烯酰甘油（2-AG），分别由神经系统中的不同酶脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）降解。FAAH 和 MAGL 抑制剂分别导致脑内 AEA 和 2-AG 水平升高，并减少啮齿动物的疼痛、焦虑和抑郁，而不会引起与直接大麻素受体-1（CB1）激动剂观察到的全部精神行为效应。这些发现激发了几类内源性大麻素水解酶抑制剂的开发，其中大多数已被优化为对 FAAH 或 MAGL 具有特异性，或者在某些情况下，对两种酶具有同等活性。在这里，我们研究了一类不寻常的 O-羟基乙酰胺碳酸酯抑制剂，发现该类中的个别化合物可作为体内 FAAH 或 FAAH/MAGL 的选择性抑制剂，在 0.125-12.5 mg kg(-1)的剂量范围内（适合行为研究）。竞争性和点击化学活性基于蛋白质谱证实，O-羟基乙酰胺碳酸酯 SA-57 在体内对 FAAH 和 MAGL 具有显著的选择性，仅靶向大脑中的另一种酶，即额外的 2-AG 水解酶 ABHD6。这些数据将 O-羟基乙酰胺碳酸酯指定为创建内源性大麻素水解酶抑制剂的多功能化学型，其在体内具有优异的活性和可调节的 FAAH-花生四烯酸胺与 MAGL（和 ABHD6）-2-AG 途径的选择性。
