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A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects.
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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) ? and ? 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 (IC?? = 690 nM) against the human recombinant DAGL?, and selectivity (IC?? > 10 ?M) 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 ?M, 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 CB? or CB? cannabinoid receptors (Ki > 10 ?M). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 ?M) 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.
SUBMITTER: Bisogno T
PROVIDER: S-EPMC3687659 | biostudies-literature | 2013 Jun
REPOSITORIES: biostudies-literature
Publications
A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects.
British journal of pharmacology 20130601 4
<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Three new fluorophosphonate compounds O-7458, O-7459 and O-7460 were ...[more]