Table Of ContentThe Endocannabinoidome
The World of Endocannabinoids
and Related Mediators
Vincenzo Di Marzo
Jenny Wang
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DEDICATIONS
To my wife, Adriana, and my daughter, Marta, for bearing with my
“obsession” with endocannabinoids and related mediators.
To the loving memory of J. Michael Walker, who, back in 2001, first
pointed out to me the possibility of the existence of so many endocan-
nabinoid-like mediators.
–Vincenzo Di Marzo
To my son Jeffrey, my parents, and my sister Xinxin and her husband
Dan.
–Jenny Wang
CONTRIBUTORS
Stephen P.H. Alexander Helle Adser Hassing
Life Sciences, University of Department of Drug Design and
Nottingham Medical School, Pharmacology, Faculty of Health
Nottingham, England and Medical Sciences, University of
Copenhagen, Copenhagen, Denmark
Michiel Balvers
Division of Human Nutrition, Daniel J. Hermanson
Wageningen University, EV A.B. Hancock Jr. Memorial
Wageningen, The Netherlands Laboratory for Cancer Research,
Departments of Biochemistry,
Heather B. Bradshaw
Chemistry, and Pharmacology,
Department of Psychological and
Vanderbilt Institute of Chemical
Brain Sciences, Indiana University,
Biology, Center in Molecular
Bloomington, Indiana, USA
Toxicology, and Vanderbilt-Ingram
Cancer Center, Nashville, Tennessee
Luciano De Petrocellis
Endocannabinoid Research Group, Philip J. Kingsley
Institute of Biomolecular Chemistry, A.B. Hancock Jr. Memorial
Consiglio Nazionale delle Ricerche, Laboratory for Cancer Research,
Pozzuoli, Naples, Italy Departments of Biochemistry,
Chemistry, and Pharmacology,
Vincenzo Di Marzo
Vanderbilt Institute of Chemical
Endocannabinoid Research Group,
Biology, Center in Molecular
Institute of Biomolecular Chemistry,
Toxicology, and Vanderbilt-Ingram
Consiglio Nazionale delle Ricerche,
Cancer Center, Nashville, Tennessee
Pozzuoli, Naples, Italy
Karen Kleberg
Harald S. Hansen
Department of Drug Design and
Department of Drug Design and
Pharmacology, Faculty of Health
Pharmacology, Faculty of Health
and Medical Sciences, University of
and Medical Sciences, University of
Copenhagen, Copenhagen, Denmark
Copenhagen, Copenhagen, Denmark
xii Contributors
Emma Leishman Kazuhito Tsuboi
Department of Psychological and Department of Biochemistry,
Brain Sciences, Indiana University, Kagawa University School of
Bloomington, Indiana, USA Medicine, Kagawa, Japan
Lawrence J. Marnett Natsuo Ueda
A.B. Hancock Jr. Memorial Department of Biochemistry,
Laboratory for Cancer Research, Kagawa University School of
Departments of Biochemistry, Medicine, Kagawa, Japan
Chemistry, and Pharmacology,
Toru Uyama
Vanderbilt Institute of Chemical
Department of Biochemistry,
Biology, Center in Molecular
Kagawa University School of
Toxicology, and Vanderbilt-Ingram
Medicine, Kagawa, Japan
Cancer Center, Nashville, Tennessee
Jenny W. Wang
Jocelijn Meijerink
Department of Biological Sciences,
Division of Human Nutrition,
Allergan Inc., Irvine, California
Wageningen University, EV
Wageningen, The Netherlands Kikuko Watanabe
Department of Nutrition,
Fabiana Piscitelli
Koshien University, Takarazuka,
Endocannabinoid Research Group,
Hyogo, Japan
Institute of Biomolecular Chemistry,
Consiglio Nazionale delle Ricerche, Renger Witkamp
Pozzuoli, Naples, Italy
Division of Human Nutrition,
Wageningen University, EV
Pierluigi Plastina
Wageningen, The Netherlands
Division of Human Nutrition,
Wageningen University, EV David F. Woodward
Wageningen, The Netherlands;
Department of Biological Sciences,
Department of Pharmaceutical
Allergan Inc., Irvine, California
Sciences, University of Calabria,
Calabria, Italy
PREFACE
Vincenzo Di Marzo, Jenny W. Wang
The discovery of two G-protein coupled receptors (GPCRs) for Cannabis
sativa psychotropic principle ∆9-tetrahydrocannabinol (THC), named
“cannabinoid” receptors, and of their endogenous lipid ligands, the en-
docannabinoids [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 “en-
docannabinoid 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
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 com-
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] 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,
xiv Preface
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 consid-
ered, at best, as mere “entourage” compounds, i.e., “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 pro-
duce 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 me-
diators 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 lipoamino-
acids), such as the N-acyl glycines and N-acyl serines [14–16], which tar-
get 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
Preface xv
redundancy emerges, which might hinder the translation of these find-
ings 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 mediators obtained from the
catalytic action of cyclooxygenase-2 and various prostaglandin syn-
thases. The ensuing metabolites, i.e., the prostaglandin ethanolamides
(or “prostamides”) and the prostaglandin glycerol esters, are emerg-
ing 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 recep-
tors, whose molecular nature is still not fully understood. The compre-
hensively updated pharmacology of prostamide F is then discussed
2a
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 biologi-
cal 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 dis-
cussed in Chapter 7 by Kikuko Watanabe and David F. Woodward, on
prostamide F , and in Chapter 8 by Natsuo Ueda, Kazuhito Tsuboi,
2a
and Toru Uyama, on NAEs and MAGs. This knowledge has already
provided, and will provide even more in the future, the bases for the de-
velopment 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 analyti-
cal methods for their measurement in tissues and biological fluids, a sub-
ject 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
xvi Preface
the endocannabinoidome. Indeed, in the last chapter of the book, Ste-
phen 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 pharmacologi-
cally relevant modulators of the same orphan GPCRs, nuclear recep-
tors, 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 complex-
ity of the endocannabinoidome and its high potential in terms of future
discoveries crucial for our understanding of how the biological func-
tions 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.
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