Therapeutic potential of the endocannabinoid system to treat chronic pain in inflammatory disease
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Therapeutic potential of the endocannabinoid system to treat chronic pain in inflammatory disease Pharma researchers Julie Blaising and Philip Smith from F. Hoffmann-La Roche Ltd. discuss the endocannabinoid system as a pathway to treat inflammatory diseases such as Inflammatory Bowel Disease (IBD) and endometriosis. The endocannabinoid system (ECS) is a complex system that comprises the cannabinoid receptors 1 and 2 (CB1 and CB2, respectively), endocannabinoid (EC) ligands, and enzymes involved in the synthesis and degradation of endocannabinoids. (1) It is broadly expressed in the body and modulates physiology and immunity. (2, 3)The endocannabinoid system comprises the two well characterized G i/o ‐protein coupled receptors (cannabinoid receptor 1 (CB1) and CB2), their endogenous lipid ligands, and the enzymes involved in their biosynthesis and biotransformation. Drug discovery efforts relating to the endocannabinoid system have been focused mainly on the two cannabinoid receptors and the two endocannabinoid deactivating enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). This review provides an overview of cannabinergic agents used in drug research and those being explored clinically.
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The endocannabinoid system (ECS) modulates a variety of physiological processes, attracting considerable attention as a potential target for therapeutic intervention. This complex system is activated by the lipid-derived mediators anandamide and 2-arachidonoyl-sn-glycerol (2-AG), which mainly engage the cannabinoid receptor subtypes 1 (CB1) and 2 (CB2). The biological actions of anandamide and 2-AG are terminated by internalization and intracellular enzymatic hydrolysis catalyzed primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), respectively. Here, we provide an overview of ECS and discuss the implications for advancing pharmacological tools that interfere with such a system as next-generation therapeutics. This review contains 4 figures, 3 tables and 41 references Keywords: Endocannabinoid; anandamide; 2-Arachidonoyl-sn-glycerol; fatty acid amide hydrolase; monoacylglycerol lipase; cannabinoid receptors; N-acylethanolamine acid amidase; Δ9-tetrahydrocannabinol.
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Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons. Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects. In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread. This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.
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The two principal endocannabinoids, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol (2-AG), are synthesized from arachidonic acid (AA) and AA is released as they are degraded. Therefore, the function of endocannabinoids is closely linked to AA, but the exact relationships have not been clarified, especially with respect to endocannabinoid metabolism. In the present study, oil rich in AA was administered (0, 100, 200 and 300 m l) orally to male mice for 7 days. Phospholipase D (PLD), fatty acid amide hydrolase (FAAH), diacyl-glycerol lipase (DAGL), monoacyl-glycerol lipase (MAGL) and cannabinoid 1 (CB1) receptor mRNA expressions were determined in the whole brain. No changes in the expression of any gene investigated were detected following AA treatment. However, it was demonstrated that the expression of the CB1 receptor was positively correlated with PLD, FAAH and DAGL expression. This suggests that expression of the CB1 receptor is closely coordinated with that of the enzymes which synthesize its ligands.
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Background: Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are signalling lipids which belong to the class of endocannabinoids (ECs) and exert their actions by activating cannabinoid receptor type-1 (CB1) and type-2 (CB2). These receptors are involved in many physiological and pathological processes in the central nervous system (CNS) and in peripheral organs. Despite many potent and selective ligands for cannabinoid receptors have been generated over the last two decades, this class of compounds achieved only a very limited therapeutic success, mainly because of the CB1- mediated side effects. Methods: The compounds and results presented in this review article have been gathered from an extensive research in public databases for patents, clinical trials and scientific literature. Reference to patent numbers, clinical trial registry numbers, websites and scientific articles is provided in the text and/or in the reference section. Results: Over the last 10-15 years, many inhibitors for the main EC hydrolytic enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α,β-hydrolase domain-6 (ABHD6) and -12 (ABHD12) have been synthesized and characterized in vitro and in vivo. Additionally, other targets have been explored for the modulation of the endocannabinoid system (ECS). Among them, several novel inhibitors for COX-2, diacylglycerol lipases and the putative endocannabinoid membrane transporter have been described in the literature. Polypharmacological approaches which combine mild or reversible inhibition of at least two of these targets are also under investigation. Conclusions: The ECS offers several therapeutic opportunities beyond the direct activation of cannabinoid receptors. The modulation of EC levels in vivo represents an interesting therapeutic perspective for several CNS-related diseases. Based on the literature and patent literature this review provides an overview of the different classes of inhibitors for FAAH, MAGL, ABHDs and COX-2 used as tool compounds and for clinical development with a special focus on CNS-related diseases. Keywords: Endocannabinoid system, endocannabinoid, anandamide, 2-arachidonoyl glycerol, FAAH, MAGL, cannabinoid receptors.
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The discriminative‐stimulus (S d ) and other behavioral effects of CB1 ligands can be reproduced in mice by combined inhibition of the anandamide‐ (AEA‐) and 2‐arachidinoyl glycerol‐ (2‐AG‐) inactivating enzymes fatty‐acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL; Long et al. 2009). The present studies using selective and non‐selective ligands [FAAH (URB 597;AM 2018), MGL (AM 2036); mixed (AM 2129), and FAAH /CB1 (AM 3506) were conducted to further explore effects of mixed FAAH and MGL inhibition in squirrel monkeys that discriminate CB1 agonists (AM 4054;THC) from vehicle (n=4). Results indicate that: 1) mixed (but not FAAH‐ or MGL‐selective) inhibition or the combination of FAAH inhibition with some CB1 activity reproduced CB1‐related S d effects, and 2) anandamide produced these effects after treatment with relatively low doses of non‐selective and FAAH‐selective enzyme inhibitors. Schild analysis of data from antagonism studies suggest some differences in the interaction of the several types of agonist effect with the CB1 receptor. The present data strengthen the idea that complementary, but not individual, actions of the endocannabinoids AEA and 2‐AG produce CB1‐related S d , and perhaps subjective, effects in primate species. Grant Funding Source : Supported by NIH/NIDA RO1‐31020
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