Bisogno, Tiziana and Mahadevan, Anu and Coccurello, Roberto and Chang, Jae Won and Allarà, Marco and Chen, Yugang and Giacovazzo, Giacomo and Lichtman, Aron and Cravatt, Benjamin and Moles, Anna and Di Marzo, Vincenzo (2013) A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects. British Journal of Pharmacology, 169 (4). pp. 784-793. ISSN 1476-5381
|
Text
BJP (2012).pdf - Published Version Download (908kB) | Preview |
Abstract
Background and Purpose The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects. Experimental Approach Three new fluorophosphonate compounds O-7458, O-7459 and O-7460 were synthesized and characterized in various enzymatic assays. The effects of O-7460 on high-fat diet intake were tested in mice. Key Results Of the new compounds, O-7460 exhibited the highest potency (IC50 = 690 nM) against the human recombinant DAGLα, and selectivity (IC50 > 10 μM) towards COS-7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity-based protein profiling confirmed that O-7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off-target’, that is, the serine hydrolase KIAA1363. O-7460 did not exhibit measurable affinity for human recombinant CB1 or CB2 cannabinoid receptors (Ki > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 μM) reduced 2-AG levels. When administered to mice, O-7460 dose-dependently (0–12 mg·kg−1, i.p.) inhibited the intake of a high-fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight. Conclusions and Implications O-7460 might be considered a useful pharmacological tool to investigate further the role played by 2-AG both in vitro and in vivo under physiological as well as pathological conditions.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | inhibitor; diacylglycerol; cannabinoid; 2-arachidonoylglycerol; serine lipase; anti-obesity effect |
| Subjects: | 500 Scienze naturali e Matematica 500 Scienze naturali e Matematica > 550 Scienze della Terra 500 Scienze naturali e Matematica > 570 Scienze della vita; Biologia |
| Depositing User: | PhD Roberto Coccurello |
| Date Deposited: | 19 Dec 2016 14:56 |
| Last Modified: | 19 Dec 2016 14:56 |
| URI: | http://eprints.bice.rm.cnr.it/id/eprint/15475 |
Actions (login required)
 |
View Item |
