In humans, two forms of diacylglycerol lipase, DAGLA and DAGLB, generate the endocannabinoid 2-arachidonoyl glycerol (2-AG) by attacking DAG at the sn-1 position. O-7460 is a selective inhibitor of 2-AG biosynthesis via DAGL (IC50 = 690 nM). It demonstrates much weaker inhibition towards human monoacylglycerol lipase and rat brain fatty acid amide hydrolase (IC50s > 10 uM) and does not bind to CB1 or CB2 cannabinoid receptors (Kis > 10 uM).1 At 0-12 mg/kg, i.p. in mice, O-7460 was reported to dose-dependently inhibit high-fat diet intake and reduce body weight.
BACKGROUND AND PURPOSE: The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) via DAG lipases (DAGL) alpha and beta 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 DAGLalpha, and selectivity (IC50 > 10 muM) 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 muM, 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 muM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 muM) 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. LINKED ARTICLES: This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http:\/\/dx.doi.org/10.1111/bph.2013.169.issue-4 & http:\/\/dx.doi.org/10.1111/bph.2012.167.issue-8.
