A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2‐arachidonoylglycerol with potential anti‐obesity effects. (27th May 2013)

• Record Type: Journal Article
• Authors: Bisogno, Tiziana; Mahadevan, Anu; Coccurello, Roberto; Chang, Jae Won; Allarà, Marco; Chen, Yugang; Giacovazzo, Giacomo; Lichtman, Aron; Cravatt, Benjamin; Moles, Anna; Di Marzo, Vincenzo
• Is Part Of: British journal of pharmacology. Volume 169:Number 4(2013:Jun.)
• Page Start: 784
• Page End: 793
• Publication Date: 2013-05-27
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12013
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12013-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12013-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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.</p> </sec> <sec id="bph12013-sec-0003" sec-type="section"> <title>Key Results</title> <p>Of the new compounds, O‐7460 exhibited the highest potency (IC<sub>50</sub> = 690 nM) against the human recombinant DAGLα, and selectivity (IC<sub>50</sub> > 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 CB<sub>1</sub> or CB<sub>2</sub> cannabinoid receptors (<italic>K</italic><sub>i</sub> > 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<sup>−1</sup>, i.p.) inhibited the intake of a high‐fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight.</p> </sec> <sec id="bph12013-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>O‐7460 might be considered a useful pharmacological tool to investigate further the role played by 2‐AG both <italic>in vitro</italic> and <italic>in vivo</italic> under physiological as well as pathological conditions.</p> </sec> <sec id="bph12013-sec-1001" sec-type="relatedArticles"> <title>Linked Articles</title> <p>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</p> </sec> </abstract>