Vincenzo Di Marzo, Jenny W. Wang
The discovery of two G-protein coupled receptors(GPCRs)for Cannabis sativa psychotropic principle A-tetrahydrocannabinol (THC), named"cannabinoid"receptors, and of their endogenous lipid ligands, the endocannabinoids[1], marked a milestone for both a century long series of mechanistic studies on the recreational/medicinal properties of this plant and its millennial history. At the turn of the century, these discoveries led to new successes as well as completely unpredicted findings, which can be summarized as follows:(1)the endogenous system composed of the cannabinoid CB1 and CB2 receptors, theendocannabinoids and the biochemical machinery to produce these lipids, also known as the "endocannabinoid system"(ECS), is one of the most pleiotropic signaling systems in vertebrates, by being involved in all aspects of mammalian physiology and pathology, and, for this same reason,it represents an attractive as well as very challenging target for the design and develop- ment of new therapeutic drugs [2]; (2)indeed,endocannabinoid-based rugs,such as rimonabant,have come to,and then gone from themarket(whereas others, such as Sativex, are still successful and being actively proposed for more than one disease target [3,4]), albeit before the many nuances and complications of the ECS were fully understood [5]; and(3) the ECSis a complicated system,also because theendocannabinoids, like many lipid mediators: (i) are biosynthesized and degraded through redundant routes and enzymes that also participate in the regulation of the levels of other endogenous signals [6] and (i) influence the activity also of noncannabinoid receptors [7].
The present bookprobably represents thefirst attempt torenderacom- prehensive overview of the complexity of the biochemistry and pharma- cology of endocannabinoids and endocannabinoid-like mediators,which are suggested by some authors[8-10]asanew"ome"initsownright,i.e., the"endocannabinoidome."Indeed, from the first chapter, authored by Harald S. Hansen, Karen Kleberg,and Helle Adser Hassing, readers are reminded that, although the ability of the two major endocannabinoids,anandamide and 2-arachidonoylglycerol (2-AG), to activate CBl and CB2 receptors was only discovered in the 1990s, these two compounds belong to two classes of metabolites, the Macylethanolamines (NAEs) and the monoacylglycerols(MAGs), which had been previously known for decades as minor lipid constituents and metabolic intermediates with unknown function of both animal and plant organisms.Yet, the authors also discuss how these endocannabinoid"congeners",initially consid- ered, at best,as mere"entourage"compounds,ie.,"accompanying"me- tabolites modulating the levels and/or action of their"more important" endocannabinoid brothers [11], have now been recognized as media- tors in their own right with more or less specific targets among orphan GPCRs, nuclear receptors, and ion channels. Furthermore, as pointed out in the subsequent chapter by Jocelijn Meijerink, Michiel Balvers, Pierluigi Plastina, and Renger Witkamp,new members of the NAE family are starting to be revealed and investigated as it emerges that di- ets rich in n-3 polyunsaturated fatty acids,such as eicosapentaenoic and docosahexaenoic acid (particularly abundant in fish and krill oils),may lead to the accumulation of these congeners. As suggested by these,as well as other authors[12], some "omega-3"fatty acid amides might produce important anti-inflammatory and anticancer actions, again via as yet unidentified noncannabinoid receptor-mediated mechanisms.
The next step forward in the discovery of endocannabinoid-like mediators is discussed in the third chapter of the book by Emma Leishman and Heather B. Bradshaw, who describe how other N-acyl amides are found in tissues where they do not necessarily play a role as endocan- nabinoids(i.e., endogenous agonists of CB1 and CB2 receptors[13]). First and foremost, the N-acyl amino acids(also known as lipoaminoacids), such as the N-acylglycines and N-acylserines[14-16], which target transient receptor potential (TRP, such as vanilloid types l-4) and voltage-activated（such as T-type Ca²）ion channels， as well as orphan GPCRs(such as GPR18);second, the -acyl dopamines and N-acyl serotonins, together with their own targets and anabolic and catabolic mechanisms, which are the specific subject of Chapter 5, by Luciano De Petrocellis and one of the two coeditors of the book, Vincenzo Di Marzo. The overall impression provided by these two chapters is that, when it comes to define the molecular targets and metabolic routes of endocannabinoid-like mediators,a very high degree of promiscuity and redundancy emerges, which might hinder the translation of these find- ings to the clinical development of new therapies.Pa\Chapter 4 by Lawrence J. Marnett,Philip J.Kingsley,and DanielJ. Hermanson is dedicated to discuss how arachidonic acid-containing members of these lipid families, particularly the endocannabinoids, an act as biosynthetic precursors of mediators obtained from the catalytic action of cyclooxygenase-2 and various prostaglandin synthases. The ensuing metabolites,i.e., the prostaglandin ethanolamides(or"prostamides")and the prostaglandin glycerol esters, are emerging as important mediators with possible feedback actions on the bio- logical effects of their respective endocannabinoid precursors, exerted via receptors distinct from both cannabinoid and prostanoid receptors, whose molecular nature is still not fully understood.The compre- hensively updated pharmacology of prostamide F,is then discussed in Chapter 6, by David F. Woodward and the other coeditor of this book,Jenny W. Wang. Thus, the discovery of endocannabinoids has branched both"vertically"and"horizontally"into the finding of often metabolically related bioactive fatty acid amides and esters,of which, however, to date we only appreciate in part their importance in biological functions.
What has been understood quite well is the biosynthetic routes and enzymes for some of the prostamides and all of the NAEs and MAGs, including anandamide and 2-AG,and the catabolic pathways of these latter lipid mediators. These achievements are comprehensively discussed in Chapter7 by Kikuko Watanabe and David F. Woodward,on prostamide F,, and in Chapter 8 by Natsuo Ueda, Kazuhito Tsuboi, and Toru Uyama, on NAEs and MAGs. This knowledge has already provided, and will provide even more in the future,the bases for the development of pharmacological(.e., enzyme inhibitors)and genetic(i.e.,"knockout"or "knockin"mice) tools, which will be crucial for the full understanding of the physiological and pathological roles of these lipid mediators, as will be the development of sensitive and accurate analytical methods for their measurement in tissues and biological fluids,a subject that is discussed in Chapter 9 by Fabiana Piscitelli Finally, perhaps the book could not be considered complete without an ideal"return"to the Cannabis plant,the root of all our knowledge of the endocannabinoidome.Indeed, in the last chapter of the book, Stephen P.H. Alexander nicely undertook the task of showing the readers how some of the emerging targets of endocannabinoid-like mediators are also shared by plant cannabinoids, and notjust THC. In fact,some"phytocannabinoids"are now also being considered as pharmacologi- cally relevant modulators of the same orphan GPCRs, nuclear receptors,and ion channels targeted by the fatty acid amides and glycerol esters, which are the protagonists of this book, and in many instances, by endocannabinoids as well. In summary, we believe that the book manages to depict the complexity of the endocannabinoidome and its high potential in terms of future discoveries crucial for our understanding of how the biological functions of living organisms are regulated by lipid mediators, and, hence, for the identification of the strategies through which this new knowledge can be translated into the development of new medicines.
REFERENCES
[1] Mechoulam R,Fride E,Di MarzoV.Endocannabinoids. EurJ Pharmacol1998;359(1):1-18.[2] Di Marzo V, Bifulco M, De Petrocellis L.The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004;3(9):771-84.[3] Scheen AJ, Paquot N. Use of cannabinoid CBI receptor antagonists for the treatment of metabolic disorders. Best Pract Res Clin Endocrinol Metab 2009;23(1):103-16. [4] Sastre-GarrigaJ, VilaC,ClissoldS,MontalbanX.THCand CBDoromucosalspray(Sativex)in the management of spasticity associated with multiple sclerosis. Expert Rev Neurother 2011;11(5):627-33.[5] Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 2008;7(5):438-55[6] Rahman IA, Tsuboi K,Uyama T,Ueda N. New players in the fatty acyl ethanolamide metabolism. Pharmacol Res 2014;86C:1-10.

Contributors xi

PrefaCe xiii

Acknowledgments xix

Chapter 1 Non-endocannabinoid NV-Acylethanolamines and Monoacylglycerols: Old Molecules New Targets 1

Harald S. Hansen, Karen Kleberg, Helle Adser Hassing

1.1 Introduction 1

1.2 Formation and Degradation of N-Acylethanolamines 2

1.3 Biological Roles and Drug Targets of Non-endocannabinoid-Acylethanolamines N-Acylethanolamines 4

1.4 Formation and Degradation of Non-endocannabinoid 2-monoacylglycerols 5

1.5 Biological Roles and Drug Targets of Non-endocannabinoid 2-monoacylglycerols 7

1.6 Conclusion 8

Acknowledgment 9

References 9

Chapter 2 Omega-3 Polyunsaturated N-Acylethanolamines: A Link Between Diet and Cellular Biolog 15

Jocelijn Meijerink,Michiel Balvers, Pierhuigi Plastina,Renger Witkamp .

2.1 Introduction 16

2.2 Modulation of the Endocannabinoidome by Dietary Fatty Acids-Biochemical Aspects 18

2.3 Effects of Diet-Animal Studies 20

2.4 Effects of Diet-Human Data 23

2.5 In vitro Formation of N-3 Fatty Acid Derived Amides 23

2.6 Biological Effects of N-3 Fatty Acid Derived NAEs and Other Amides 24

2.7 Conclusions and Future Perspectives 28

References 29

Chapter 3 N-Acyl Amides: Ubiquitous Endogenous Cannabimimetic Lipids That Are in the Right Place at the Right Time 33

Enma Leishman, Heather B. Bradshaw

3.1 N-Acyl Amides: All in the Family 33

3.2 GPR18 39

3.3 N-Acyl Amides/Endogenous Cannabinoids that Activate TRP Receptors 39

3.4 N-Acyl Amide/eCBs with not Yet Identified Phytocannabinoid Ligands 44

3.5 Nowhere to Go But Up 45

References 45

Chapter 4 Oxidative Metabolites of Endocannabinoids Formed by Cyclo0xygenase-2 49 Lawrence J. Marnett,Philip J. Kingsley, Daniel J. Hermanson

4.1 COX-2 Metabolism of Endocannabinoids 50

4.2 Analysis of ECs and their COX-2 Metabolites 52

4.3 Tools to Study PG-G and PG-EA Functions 55

4.4 Biological Effects of PG-Gs and PG-EAs 57

4.5 Perspective 60

References 62

Chapter 5 N-Acyldopamines and N-Acylserotonins: From Synthetic Pharmacological Tools to Endogenous Multitarget MediatorS 67

Luciano De Petrocellis, Vincenzo Di Marzo

5.1 Introduction 67

5.2 N-Acyldopamines 68

5.3 N-Acylserotonins 75

5.4 Conclusions 78

References 79

Chapter 6 The Pharmacology of Prostaglandin F2a, Ethanolamide and Bimatoprost Reveals a Unique Feedback Mechanism on Endocannabinoid Actions 85

David F. Woodward, Jenny W. Wang

6.1 Introduction 85

6.2 Pharmacology 86

6.3 Endogenous Prostamide PGF2a 87

6.4 Prostamide Receptor Detection 89

6.5 Biological Function and Therapeutics 90

Acknowledgment 96

References 96

Chapter 7 Prostamide F2a,Biosynthesizing Enzymes 101

Kikuko Watanabe,David F. Woodward

7.1 Introduction 101

7.2 PGF Synthases Belonging to the Aldo-Keto Reductase Superfamily: Molecular Structure and Properties 102

7.3 Prostamide/PGF Synthase: Properties 103

7.4 AkR1C3 and Related PGF Synthases and Prostamide/PGF Synthase: Substrates and Inhibitors 104

7.5 Comparative Distribution of AkR1C3 and Related AkR Enzymes with Prostamide/PGF Synthase 105

7.6 Prostamide/PGF Synthase AkR1C3 and Related PGF Synthases and their Relation to Biological Function and Therapeutics 106

References 108

Chapter 8 Metabolic Enzymes for Endocannabinoids and Endocannabinoid-Like Mediators 111

Natsuo Ueda, Kazuhito Tsuboi, Toru Uyama

8.1 Introduction 111

8.2 Enzymes for the Biosynthesis of N-Acylethanolamines 112

8.3 Enzymes for the Degradation of N-Acylethanolamines 118

8.4 Enzymes for the Biosynthesis of 2-AG 122

8.5 Enzymes for the Degradation of 2-AG 124

8.6 Perspectives 127

References 127

Chapter 9 Endocannabinoidomics: "Omics"Approaches Applied to Endocannabinoids and Endocannabinoid-Like Mediators 137

Fabiana Piscitelli

9.1 Introduction 137

9.2 Biochemistry and Pharmacology of Endocannabinoids and Endocannabinoid-Related Compounds 138

9.3 Lipidomics in"Endocannabinoidomics": Mass-Spectrometric Approaches for Endocannabinoid and Endocannabinoid-Like Molecule Quantification 141

9.4 New Frontiers 147

9.5 Conclusions 148

References 149

Chapter 10 Common Receptors for Endocannabinoid-Like Mediators and Plant Cannabinoids 153

Stephen P.H. Alexander

10.1Introduction 153

10.2 CB and CB, Receptors 154

10.3 Beyond CB,and CB,Receptors: Cannabinoid Receptor-Like GPCR 106

10.4 Ligand- and Voltage-Gated ion Channels 160

10.5 Nuclear Hormone Receptors 160

10.6 Amplification of Endocannabinoid Tone 165

10.7 Concluding Remarks 167

References 167

Index 177

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