Preface

Vincenzo Di Marzo

Jenny W. Wang

The discovery of two G-protein coupled receptors (GPCRs) for Cannabis sativa psychotropic principle Δ9 -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, the endocannabinoids 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 development of new therapeutic drugs [2]; (2) indeed, endocannabinoid-based drugs, such as rimonabant, have come to, and then gone from the market (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 ECS is a complicated system, also because the endocannabinoids, 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 (ii) influence the activity also of noncannabinoid receptors [7].

The present book probably represents the first attempt to render a comprehensive overview of the complexity of the biochemistry and pharmacology of endocannabinoids and endocannabinoid-like mediators, which are suggested by some authors [8–10] as a new “ome” in its own right, 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 CB1 and CB2 receptors was only discovered in the 1990s, these two compounds belong to two classes of metabolites, the N-acylethanolamines (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 considered, at best, as mere “entourage” compounds, i.e., “accompanying” metabolites modulating the levels and/or action of their “more important” endocannabinoid brothers [11], have now been recognized as mediators 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 diets 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 endocannabinoids (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-acyl glycines and N-acyl serines [14–16], which target transient receptor potential (TRP, such as vanilloid types 1–4) and voltage-activated (such as T-type Ca2+) ion channels, as well as orphan GPCRs (such as GPR18); second, the N-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 findings to the clinical development of new therapies.

Chapter 4 by Lawrence J. Marnett, Philip J. Kingsley, and Daniel J. Hermanson is dedicated to discuss how arachidonic acid-containing members of these lipid families, particularly the endocannabinoids, can act as biosynthetic precursors of fatty acid amide and glycerol ester 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 biological 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 comprehensively updated pharmacology of prostamide F2α 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 Chapter 7 by Kikuko Watanabe and David F. Woodward, on prostamide F2α, 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 (i.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 not just THC. In fact, some “phytocannabinoids” are now also being considered as pharmacologically 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.