| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 14, 2010
Contents
Endocannabinoid-Binding Receptors:
Old Friends and New Comers
Guest Editor: Mauro Maccarrone
Editorial Pp. 1339-1340
[PMID: 20441559 PubMed - indexed for MEDLINE]
Novel Natural and Synthetic
Ligands of the Endocannabinoid System Pp. 1341-1359
L.O. Hanuš and R. Mechoulam
[Abstract] [Purchase
Article] [PMID: 20166928 PubMed - indexed for MEDLINE]
Receptors and Channels Targeted by Synthetic Cannabinoid Receptor
Agonists and Antagonists Pp. 1360-1381
R.G. Pertwee
[Abstract] [Purchase
Article] [PMID: 20166927 PubMed - indexed for MEDLINE]
CB1 Cannabinoid Receptors
and their Associated Proteins Pp. 1382-1393
A.C. Howlett, L.C. Blume and G.D. Dalton
[Abstract] [Purchase
Article] [PMID: 20166926 PubMed - indexed for MEDLINE]
Cannabinoid CB2 Receptors
in Health and Disease Pp. 1394-1410
K.D. Patel, J.S. Davison, Q.J. Pittman and K.A.
Sharkey
[Abstract] [Purchase
Article] [PMID: 20166925 PubMed - indexed for MEDLINE]
GPR55: Current Knowledge and Future Perspectives of
a Purported “Type-3” Cannabinoid Receptor
Pp. 1411-1429
A. Moriconi, I. Cerbara, M. Maccarrone and A.
Topai
[Abstract]
[Purchase
Article] [PMID: 20166924 PubMed - indexed for MEDLINE]
Endocannabinoids as Regulators of Transient Receptor Potential
(TRP) Channels: a Further Opportunity to Develop New Endocannabinoid-Based
Therapeutic Drugs Pp. 1430-1449
V. Di Marzo and L. De Petrocellis
[Abstract]
[Purchase
Article] [PMID: 20166923 PubMed - indexed for MEDLINE]
From Surface to Nuclear Receptors: The Endocannabinoid Family
Extends its Assets Pp. 1450-1467
M. Pistis and M. Melis
[Abstract] [Purchase
Article] [PMID: 20166922 PubMed - indexed for MEDLINE]
Endocannabinoid Binding
to the Cannabinoid Receptors: What Is Known and What Remains
Unknown Pp. 1468-1486
P.H. Reggio
[Abstract] [Purchase
Article] [PMID: 20166921 PubMed - indexed for MEDLINE]
Interaction of Endocannabinoid Receptors with Biological Membranes
Pp. 1487-1499
E. Dainese, S. Oddi and M. Maccarrone
[Abstract] [Purchase
Article] [PMID: 20166920 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [PMID: 20441559 PubMed - indexed for MEDLINE]
Editorial: Endocannabinoid-Binding Receptors: Old Friends
and New Comers
The plant Cannabis sativa produces ~80 terpeno-phenol
compounds, termed “phytocannabinoids”, among which
Δ9-tetrahydrocannabinol
(THC) is the most psychotropic component [1]. THC binds to
specific G-protein-coupled receptors (GPCRs), named type-1
(CB1) and type-2 (CB2)
cannabinoid receptors, that are also activated by endogenous
ligands called “endocannabinoids” (eCBs). Among
these lipid substances anandamide (N-arachidonoylethanolamine,
AEA) was discovered as the first endogenous ligand of CB1
receptors, the most abundant GPCRs in mammalian brain. AEA
is a prototype member of fatty acid amides, whereas 2-arachidonoylglycerol
(2-AG) is the most prominent representative of monoacylglycerols,
another group of eCBs [2]. Since the discovery of AEA and
2-AG, eCBs have received ever increasing attention, and their
anti-cancer, anti-ischemic, anti-inflammatory, anti-depressant,
anxiolytic, anorectic and bone-stimulant actions (just to
list a few) are now widely recognized. This background has
boosted pharmacological research, aimed at exploiting the
therapeutic potential of eCBs-oriented drugs for the treatment
of several diseases, both centrally and peripherally [3, 4].
AEA, 2-AG and other congeners interact with members of at
least three of the four major classes of receptor proteins:
GPCRs, ion channels (including ligand-gated ion channels),
and nuclear receptors. In this context, it seems noteworthy
that eCBs are able to interact with their receptors at binding
sites exposed either extracellularly or intracellularly, and
located within lipid rafts or in non-rafts microdomains [5].
Such a wealth of possibilities seems to underpin the critical
role of eCBs-binding receptors in intra- and inter-cellular
signalling [6, 7]. On this basis, eCBs-binding receptors are
the focus of this Hot Topic issue of Current
Medicinal Chemistry, where an update on CB1
[8] and CB2 [9] receptors
will be presented, along with an overview of the other well-established
target of AEA, the ion channel TRPV1 (transient receptor potential
vanilloid-1) [10]. Furthermore, the actions of eCBs that engage
nuclear receptors like peroxisome proliferator-activated receptors
[11], and the pros and cons of the "orphan"
G-protein-coupled receptor GPR55 as a true “type-3”
(CB3) cannabinoid receptor
will be discussed [12]. Overall, a complete survey of the
eCBs-binding receptors best characterized to date will be
presented. In addition, it should be stressed that even more
candidates are emerging as targets of eCBs, like the transient
receptor potential of melastatin-type 8 (TRPM8), that is antagonized
by AEA [13], or the GPR119, which can recognize N-oleoylethanolamine
and N-palmitoylethanolamine that are not ligands
at classical CB receptors [14]. It seems evident that such
a variety of potential triggers of endocannabinoid signalling
has been disclosed by means of selective synthetic agonists
or antagonists [15], and implies per se a variety
of natural ligands in different cell types [16]. Furthermore,
the determinants of ligand recognition by different receptors
will be addressed in this Hot Topic issue [17], as
will be the role of the membrane environment in ligand-receptor
interaction [18].
Overall, I hope that this book can represent a useful instrument
for the broad readership of Current Medicinal Chemistry,
in order to get acquainted with one of the most exciting classes
of molecules discovered at the end of the last millennium:
the endocannabinoids. I expect that reading the chapters written
by leading experts might foster novel ideas and boost new
collaborations within the scientific community.
I wish to dedicate this book to Claudia, Giuseppe and Gianna.
REFERENCES
[1] Izzo, A.A.; Borrelli, F.; Capasso, R.; Di Marzo, V.; Mechoulam,
R. Non-psychotropic plant cannabinoids: new therapeutic opportunities
from an an-cient herb. Trends Pharmacol. Sci.
2009, 30, 515-527.
[2] Petrosino, S.; Ligresti, A.; Di Marzo, V. Endocannabinoid
chemical biology: a tool for the development of novel therapies.
Curr. Opin. Chem. Biol. 2009,
13, 309-320.
[3] Hill, M.N.; Hillard, C.J.; Bambico, F.R.; Patel, S.; Gorzalka,
B.B.; Gobbi, G. The therapeutic potential of the endocannabinoid
system for the devel-opment of a novel class of antidepressants.
Trends Pharmacol. Sci. 2009, 30,
484-493.
[4] Maccarrone, M. Endocannabinoids: Friends and foes of reproduction.
Prog. Lipid Res. 2009, 48,
344-354.
[5] Dainese, E.; Oddi, S.; Maccarrone, M. Lipid-mediated dimerization
of beta2-adrenergic receptor reveals important clues for cannabinoid
receptors. Cell. Mol. Life Sci. 2008,
65, 2277-2279.
[6] Centonze, D.; Battistini, L.; Maccarrone, M. The endocannabinoid
system in peripheral lymphocytes as a mirror of neuroinflammatory
diseases. Curr. Pharm. Des. 2008,
14, 2370-2382.
[7] Katona, I.; Freund, T.F. Endocannabinoid signaling as
a synaptic circuit breaker in neurological disease. Nat.
Med. 2008, 14, 923-930.
[8] Howlett, A.C.; Blume, L.C.; Dalton, G.D. CB1 cannabinoid
receptors and their associated proteins. Curr. Med. Chem.
2010, in press.
[9] Patel, K.D.; Davison, J.S.; Pittman, Q.J.; Sharkey, K.A.
Cannabinoid CB2 receptors. Curr. Med. Chem. 2010,
in press.
[10] Di Marzo, V.; De Petrocellis, L. Endocannabinoids as
regulators of transient receptor potential (TRP) channels:
a further opportunity to develop new endocannabinoid-based
therapeutic drugs. Curr. Med. Chem. 2010,
in press.
[11] Pistis, M.; Melis, M. From surface to nuclear receptors:
the endocannabinoid family extends its assets. Curr. Med.
Chem. 2010, in press.
[12] Moriconi, A.; Cerbara, I.; Maccarrone, M.; Topai, A.
GPR55: current knowledge and future perspectives of a purported
“type-3” cannabinoid receptor. Curr. Med.
Chem. 2010, in press.
[13] De Petrocellis, L.; Starowicz, K.; Moriello, A.S.; Vivese,
M.; Orlando, P.; Di Marzo, V. Regulation of transient receptor
potential channels of melastatin type 8 (TRPM8): effect of
cAMP, cannabinoid CB1 receptors and endovanilloids. Exp.
Cell Res. 2007, 313, 1911-1920.
[14] Godlewski, G.; Offertáler, L.; Wagner, J.A.; Kunos,
G. Receptors for acylethanolamides-GPR55 and GPR119. Prostaglandins
Other Lipid Mediat. 2009, 89,
105-111.
[15] Pertwee, R.G. Receptors and channels targeted by synthetic
cannabinoid receptor agonists and antagonists. Curr. Med.
Chem. 2010, in press.
[16] Lumír, O.H.; Mechoulam, R. Novel natural and synthetic
ligands of the endocannabinoid system. Curr. Med. Chem.
2010, in press.
[17] Reggio, P.H. Endocannabinoid binding to the cannabinoid
receptors: What is known and what remains unknown. Curr.
Med. Chem. 2010, in press.
[18] Dainese, E.; Oddi, S.; Maccarrone, M. Interaction of
endocannabinoid receptors with biological membranes. Curr.
Med. Chem. 2010, in press.
Mauro Maccarrone
Department of Biomedical Sciences
University of Teramo
Piazza Aldo Moro 45
64100 Teramo, Italy
& Santa Lucia Foundation, Rome, Italy
Tel: 39-0861-266875
Fax: 39-0861-266877
E-mail: mmaccarrone@unite.it
[Back to top] [Purchase
Article] [PMID: 20166928 PubMed - indexed for MEDLINE]
Novel Natural and Synthetic
Ligands of the Endocannabinoid System
L.O. Hanuš and R. Mechoulam
In this review we describe recent advances in the chemistry
of novel CB1/CB2
agonists, CB1 antagonists,
selective CB2 agonists, fatty
acid amide hydrolase inibitors, monoglyceride (MGL) and diglyceride
(DAGL) inhibitors and cannabinoid-type agonists and antagonists
of non CB1/CB2
receptors. In view of recent interest in the activities of
fatty acid amides of amino acids (N-acyl amino acids) a list
of this type of compounds was compiled and is presented as
a Table. We conclude that further synthetic work based on
both the plant cannabinoids and on the endocannabinoids may
lead to novel therapeutics and that the identification and
the elucidation of the biological profile of the myriad of
endogenous N-acyl amino acids and related compounds may enhance
the already wide spectrum of lipidomics.
[Back to top]
[Purchase
Article] [PMID: 20166927 PubMed - indexed for MEDLINE]
Receptors and Channels Targeted by Synthetic Cannabinoid Receptor
Agonists and Antagonists
R.G. Pertwee
It is widely accepted that non-endogenous compounds that target
CB1 and/or CB2
receptors possess therapeutic potential for the clinical management
of an ever growing number of disorders. Just a few of these
disorders are already treated with Δ9-tetrahydrocannabinol
or nabilone, both CB1/CB2
receptor agonists, and there is now considerable interest
in expanding the clinical applications of such agonists and
also in exploiting CB2-selective
agonists, peripherally restricted CB1/CB2
receptor agonists and CB1/CB2
antagonists and inverse agonists as medicines. Already, numerous
cannabinoid receptor ligands have been developed and their
interactions with CB1 and
CB2 receptors well characterized.
This review describes what is currently known about the ability
of such compounds to bind to, activate, inhibit or block non-CB1,
non-CB2 G protein-coupled
receptors such as GPR55, transmitter gated channels, ion channels
and nuclear receptors in an orthosteric or allosteric manner.
It begins with a brief description of how each of these ligands
interacts with CB1 and/or
CB2 receptors.
[Back to top]
[Purchase
Article] [PMID: 20166926 PubMed - indexed for MEDLINE]
CB1 Cannabinoid Receptors
and their Associated Proteins
A.C. Howlett, L.C. Blume and G.D. Dalton
CB1 receptors are G-protein
coupled receptors (GPCRs) abundant in neurons, in which they
modulate neurotransmission. The CB1
receptor influence on memory and learning is well recognized,
and disease states associated with CB1
receptors are observed in addiction disorders, motor dysfunction,
schizophrenia, and in bipolar, depression, and anxiety disorders.
Beyond the brain, CB1 receptors
also function in liver and adipose tissues, vascular as well
as cardiac tissue, reproductive tissues and bone. Signal transduction
by CB1 receptors occurs through
interaction with Gi/o proteins to inhibit adenylyl cyclase,
activate mitogen-activated protein kinases (MAPK), inhibit
voltage-gated Ca2+ channels,
activate K+ currents (Kir),
and influence nitric oxide (NO) signaling. CB1
receptors are observed in internal organelles as well as plasma
membrane. β-Arrestins,
adaptor protein AP-3, and G-protein receptor-associated sorting
protein 1 (GASP1) modulate cellular trafficking. Cannabinoid
Receptor Interacting Protein1a (CRIP1a) is an accessory protein
whose function has not been delineated. Factor Associated
with Neutral sphingomyelinase (FAN) regulates ceramide signaling.
Such diversity in cellular signaling and modulation by interacting
proteins suggests that agonists and allosteric modulators
could be developed to specifically regulate unique, cell type-specific
responses.
[Back to top]
[Purchase Article] [PMID: 20166925 PubMed - indexed for MEDLINE]
Cannabinoid CB2 Receptors
in Health and Disease
K.D. Patel, J.S. Davison, Q.J. Pittman and K.A.
Sharkey
Marijuana has been used for thousands of years to affect human
health. Dissecting the peripheral effects from the central
psychotropic effects has revealed a complex interplay between
cannabinoids, endocannabinoids and their receptors. This review
examines recent advances in understanding the expression,
regulation and utilization of the CB2
receptor. Here we highlight the molecular aspects of the CB2
receptor, CB2 receptor signaling
and new ligands for this receptor. We focus in the rest of
the review on recent findings in the immune system, the gastrointestinal
tract and liver, the brain and the cardiovascular system and
airways as examples of areas where new developments in our
understanding of the CB2
receptor have occurred. Early studies focused on expression
of this receptor under baseline physiologic conditions; however,
perturbations such as those that occur during inflammation,
ischemia/reperfusion injury and cancer are revealing a critical
role for the CB2 receptor
in regulating these disease processes amongst others. As a
result, the CB2 receptor
is an appealing therapeutic target as well as a useful tool
for shedding new light on physiological regulatory processes
throughout the body.
[Back to top]
[Purchase
Article] [PMID: 20166924 PubMed - indexed for MEDLINE]
GPR55: Current Knowledge and Future Perspectives of
a Purported “Type-3” Cannabinoid Receptor
A. Moriconi, I. Cerbara, M. Maccarrone and A.
Topai
In the last decade, accumulated evidence highlighted
that GPR55 might be activated by several classical cannabinoid
ligands, making this orphan receptor the main candidate to
be considered as the “third” cannabinoid receptor.
The investigation of its pharmacology has often provided divergent
and more intricate results, that have complicated the understanding
of the physiological role of GPR55. Nevertheless, the patent
analysis regarding GPR55 outlines the fair interest of big
pharmaceutical companies, especially in the first years of
this decade.
This investigation provides a brief overview of the current
“state of the art” of our knowledge of GPR55,
giving particular emphasis to its functional selectivity.
This property could account for controversial roles of GPR55,
whose pharmacology and downstream signaling is known to vary
significantly both in ligand- and system-dependent manners.
In addition, we gain insights into the challenging aspect
of finding out novel GPR55 modulators, by analyzing conserved
structural and functional motifs that, together with future
studies, could help to elucidate its mechanism of action and
to design more selective and potent small-molecules directed
towards GPR55. Preliminary data highlight remarkable differences,
but also intriguing commonalities, between GPR55 and other
members of class A G-protein-coupled receptors. It is anticipated
that, in the next future, novel lead candidates targeting
GPR55 could represent new tools to better understand GPR55-mediated
human diseases and, hopefully, generate an innovative class
of effective next-generation therapeutics.
[Back to top] [Purchase
Article] [PMID: 20166923 PubMed - indexed for MEDLINE]
Endocannabinoids as Regulators of Transient Receptor Potential
(TRP) Channels: a Further Opportunity to Develop New Endocannabinoid-Based
Therapeutic Drugs
V. Di Marzo and L. De Petrocellis
In the late 1990’s, a series of experiments carried
out independently in two laboratories led to establish an
important connection between the function of the endocannabinoids,
which, as exemplified in this special issue, is per se
very complex and ubiquitous in animals, and that of the transient
receptor potential (TRP) channels, a large family of plasma
membrane cation channels involved in several mammalian and
non-mammalian physiological and pathological conditions, overlapping
only in part with those in which the cannabinoid receptors
participate. These experiments were initially based on the
observation that the endocannabinoid anandamide and the xenobiotic
ligand of TRP channels of V1 type (TRPV1), capsaicin, are
somehow chemically similar, both compounds being fatty acid
amides, as are also synthetic activators of these channels
and inhibitors of anandamide cellular re-uptake. As discussed
in this article, the same type of “chemical thoughts”
led to the discovery of N-arachidonoyl-dopamine,
an endogenous ligand of TRPV1 channels that behaves also an
endocannabinoid. The overlap between the ligand recognition
properties of some TRP channels and proteins of the endocannabinoid
system, namely the cannabinoid receptors and the proteins
and enzymes catalyzing anandamide cellular re-uptake and hydrolysis,
is being actively explored through the rational design and
synthesis of new endocannabinoid-based drugs with multiple
mechanisms of action. These aspects are discussed in this
review article, together with the possible functional and
pharmacological consequences of endocannabinoid-TRP channel
interactions.
[Back to top] [Purchase
Article] [PMID: 20166922 PubMed - indexed for MEDLINE]
From Surface to Nuclear Receptors: The Endocannabinoid Family
Extends its Assets
M. Pistis and M. Melis
Peroxisome proliferator-activated receptors (PPARs) have long
been known as mediators of several physiological functions,
among which the best characterized are lipid metabolism, energy
balance and anti-inflammation. Their rather large and promiscuous
ligand binding site has been recently discovered to accommodate,
among a plethora of lipid molecules and metabolic intermediates,
endocannabinoids and their cognate compounds, specifically
belonging to theN-acylethanolamine group. In fact, oleoylethanolamide,
palmitoylethanolamide and probably anandamide bind with relatively
high affinity to PPARs and have now been included among their
endogenous ligands. Through activation of PPARs these molecules
exert a variety of physiological processes. Particularly,
both long-term effects via genomic mechanisms and
rapid non-genomic actions have been described, which in several
instances are opposite to those evoked by activation of “classical”
surface cannabinoid receptors.
In this review, we describe how these effects are relevant
under diverse physiological and pathophysiological circumstances,
such as lipid metabolism and feeding behaviour, neuroprotection
and epilepsy, circadian rhythms, addiction and cognition.
A picture is emerging where nuclear receptors are involved
in anorexiant, anti-inflammatory, neuroprotective, anti-epileptic,
wakefulness- and cognitive-enhancing, and anti-addicting properties
of endocannabinoid-like molecules. Further studies are necessary
to fully understand cellular mechanisms underlying the interactions
between endocannabinoids and PPARs, but also between their
surface and nuclear receptors, and to exploit their potential
therapeutic applications.
[Back to top] [Purchase
Article] [PMID: 20166921 PubMed - indexed for MEDLINE]
Endocannabinoid Binding
to the Cannabinoid Receptors: What Is Known and What Remains
Unknown
P.H. Reggio
The cannabinoid CB1 and CB2 receptors are Class A G protein-coupled
receptors (GPCRs). While many Class A GPCRs have endogenous
ligands that are hydrophilic cations (e.g., the serotonin
and dopamine receptors), the cannabinoid receptors have neutral,
highly lipophilic ligands derived from the fatty acid, arachidonic
acid. The most well-studied of these are N-arachidonoylethanolamine
(anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). This
review focuses on the experimental and computational studies
that have been used to probe the nature of endocannabinoid
interaction with the cannabinoid receptors. These studies
include mutation, SAR and NMR studies, as well as, QSAR, docking
and molecular dynamics simulations. Gaps in our knowledge
are identified. The review begins more generally, however,
by discussing the entire endocannabinoid system, of which
the cannabinoid receptors are part. For in order to understand
endocannabinoid action, one needs an appreciation for the
environments for which these ligands have been designed and
the conformational changes these ligands must undergo in order
to act on the cannabinoid receptors.
[Back to top]
[Purchase
Article] [PMID: 20166920 PubMed - indexed for MEDLINE]
Interaction of Endocannabinoid Receptors with Biological Membranes
E. Dainese, S. Oddi and M. Maccarrone
Cellular signaling is regulated by several biochemical reactions,
whose dynamics depends on changes in the fluxes of specific
ligands through the containment barriers that are the biological
membranes. The regulation of this complex dynamic equilibrium
is mainly due to the activity of border proteins, that must
be able to interact simultaneously with the lipid bilayer
and the extracellular milieu. Endocannabinoid receptors, that
include type-1 and type-2 cannabinoid receptors, the transient
vanilloid potential receptors and the peroxisome proliferator-activated
receptors, represent one of the most intriguing examples of
“border” proteins. They have also been identified
as important drug discovery targets with potential therapeutic
applications, including antiemesis, appetite enhancement,
analgesia, glaucoma treatment, and immune suppression. However,
as yet the molecular details of endocannabinoid receptor regulation
remain elusive. In this review we summarize the most relevant
aspects of the structural/functional characterization of these
receptors, with a focus on the active role played by biological
membranes (in particular lipid rafts) in the modulation of
their accessibility and mode of ligand binding. Based on available
evidence, we propose that endocannabinoid receptors can be
regulated by the rate of interlayer exchange and lateral diffusion
of endocannabinoid/cholesterol complexes within lipid bilayers,
thus suggesting innovative approaches for the therapeutic
exploitation of the membrane component of endocannabinoid
signaling.
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