Synthesis and Pharmacological Activity of a Potent Inhibitor of the Biosynthesis of the Endocannabinoid 2‐Arachidonoylglycerol

Bisogno, Tiziana; Burston, James J.; Rai, Ravi; Allarà, Marco; Saha, Bijali; Mahadevan, Anu; Razdan, Raj K.; Wiley, Jenny L.; Marzo, Vincenzo Di

doi:10.1002/cmdc.200800442

Cited by 47 publications

(40 citation statements)

References 21 publications

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“…Bisogno et al also developed MAFP organophosphorus analogs O-3640 and O-3841 that showed high selectivity for DAGLα over DAGLβ and other lipases but had poor potency, lack of stability, and poor cell penetrance 38 . Further medicinal chemistry studies improved upon O-3841, yielding the similarly potent O-5596 but with better bioavailability and stability in physiological buffers 40 . Interestingly, O-5596-treated mice displayed a significant decrease in ad libitum consumption of sweetened cereal, but not regular chow, compared to vehicle-treated mice.…”

Section: Generation Of Inhibitors For 2-ag Degradation and Synthesismentioning

confidence: 99%

Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids

Kohnz

Nomura

2014

Chem. Soc. Rev.

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The endocannabinoid system, most popularly known as the target of the psychoactive component of marijuana, Δ9-tetrahydrocannabinol (THC), is a signaling network that modulates a diverse range of physiological processes including nociception, behavior, cognitive function, appetite, metabolism, motor control, memory formation, and inflammation. While THC and its derivatives have garnered notoriety in the eyes of the public, the endocannabinoid system is consists of two endogenous signaling lipids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide) that activate cannabinoid receptors CB1 and CB2 in the nervous system and peripheral tissues. This review will focus on recent efforts to chemically manipulate 2-AG signaling, through the development of inhibitors of the 2-AG-synthesizing enzyme diacylglycerol lipase (DAGL) or the 2-AG-degrading enzyme monoacylglycerol lipase (MAGL), and assessing the therapeutic potential of DAGL and MAGL inhibitors in pain, inflammation, degenerative diseases, tissue injury, and cancer.

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Section: Generation Of Inhibitors For 2-ag Degradation and Synthesismentioning

confidence: 99%

Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids

Kohnz

Nomura

2014

Chem. Soc. Rev.

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“…In addition, the development of 'neutral' CB 1 antagonists, that do not show any significant signs of inverse agonism, has provided very promising results at the preclinical level, particularly in terms of their reversal of insulin and leptin resistance (105) . Furthermore, in the light of the fact that the increased endocannabinoid tone observed in metabolic disorders can be attributed to increased endocannabinoid biosynthesis, an alternative strategy to regulate dysregulated endocannabinoid tone in obesity might be to use DAGL inhibitors with consequent reduction in 2-AG biosynthesis (106) . Finally, changes in diet can be beneficial in preventing the onset of both obesity and other metabolic disorders.…”

Section: Endocannabinoids In Obesitymentioning

confidence: 99%

PUFA-derived endocannabinoids: an overview

Cascio

2013

Proc. Nutr. Soc.

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Following on from the discovery of cannabinoid receptors, of their endogenous agonists (endocannabinoids) and of the biosynthetic and metabolic enzymes of the endocannabinoids, significant progress has been made towards the understanding of the role of the endocannabinoid system in both physiological and pathological conditions. Endocannabinoids are mainly n-6 long-chain PUFA (LCPUFA) derivatives that are synthesised by neuronal cells and inactivated via a two-step process that begins with their transport from the extracellular to the intracellular space and culminates in their intracellular degradation by hydrolysis or oxidation. Although the enzymes responsible for the biosynthesis and metabolism of endocannabinoids have been well characterised, the processes involved in their cellular uptake are still a subject of debate. Moreover, little is yet known about the roles of endocannabinoids derived from n-3 LCPUFA such as EPA and DHA. Here, I provide an overview of what is currently known about the mechanisms for the biosynthesis and inactivation of endocannabinoids, together with a brief analysis of the involvement of the endocannabinoids in both food intake and obesity. Owing to limited space, recent reviews will be often cited instead of original papers.

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“…Throughout the review, the focus has been on compounds enhancing eCB signalling, but there are of course situations where a reduction of eCB signalling by blockade of eCB synthesis may be better (for a review, see Di Marzo 2008). Most work in this area has focussed upon identifying the eCBs involved in physiological processes such as retrograde signalling, neuronal development (see review by Oudin et al 2011), pain (Ho et al 2011; see also Gregg et al 2012) and food intake (Bisogno et al 2009a. However, blockade of eCB synthesis may also be neuroprotective in certain circumstances (Valdeolivas et al 2013).…”

Section: Discussionmentioning

confidence: 98%

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Fowler

2015

Handbook of Experimental Pharmacology

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The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

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Synthesis and Pharmacological Activity of a Potent Inhibitor of the Biosynthesis of the Endocannabinoid 2‐Arachidonoylglycerol

Cited by 47 publications

References 21 publications

Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids

Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids

PUFA-derived endocannabinoids: an overview

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

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