A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects.

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.

• Authors: Tiziana Bisogno, Anu Mahadevan, Roberto Coccurello, Jae Won Chang, Marco Allarà, Yugang Chen, Giacomo Giacovazzo, Aron Lichtman, Benjamin Cravatt, Anna Moles, Vincenzo Di Marzo
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 169 Issue 4 Pg. 784-93 (Jun 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23072382 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• 1-((fluoro(methyl)phosphoryl)oxy)-3-isopropoxypropan-2-yl oleate
• Anti-Obesity Agents
• Arachidonic Acids
• Endocannabinoids
• Enzyme Inhibitors
• Glycerides
• Glycerophospholipids
• Nerve Tissue Proteins
• Oleic Acids
• Organophosphonates
• Recombinant Proteins
• glyceryl 2-arachidonate
• Nceh1 protein, mouse
• Sterol Esterase
• DAGLA protein, human
• Lipoprotein Lipase

Topics

• Animals
• Anti-Obesity Agents (administration & dosage, pharmacology, therapeutic use)
• Arachidonic Acids (antagonists & inhibitors, metabolism)
• Behavior, Animal (drug effects)
• Cell Line
• Chlorocebus aethiops
• Dose-Response Relationship, Drug
• Endocannabinoids (antagonists & inhibitors, metabolism)
• Energy Intake (drug effects)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Glycerides (antagonists & inhibitors, metabolism)
• Glycerophospholipids (administration & dosage, pharmacology, therapeutic use)
• Humans
• Hypothalamus (drug effects, enzymology, metabolism)
• Lipoprotein Lipase (antagonists & inhibitors, genetics, metabolism)
• Liver (drug effects, enzymology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Tissue Proteins (antagonists & inhibitors, genetics, metabolism)
• Neurons (drug effects, enzymology, metabolism)
• Obesity (drug therapy, enzymology, metabolism)
• Oleic Acids (administration & dosage, pharmacology, therapeutic use)
• Organophosphonates (administration & dosage, pharmacology, therapeutic use)
• Rats
• Recombinant Proteins (chemistry, metabolism)
• Sterol Esterase (antagonists & inhibitors, metabolism)