Mini-Reviews in Medicinal Chemistry, Volume 5, No. 7, 2005
Contents
Cannabinoids
Executive
Editor: Maria L. Lopez-Rodriguez
Editorial Pp.607-607
Maria L. Lopez-Rodriguez
Therapeutic Potential of the Endocannabinoid
System in the Brain
Pp.609-617
Jose
Antonio Ramos, Sara Gonzalez, Onintza Sagredo, Maria Gomez-Ruiz and Javier
Fernandez-Ruiz
Signal Transduction Activated by Cannabinoid
Receptors Pp.619-630
Ines
Diaz-Laviada and Lidia Ruiz-Llorente
CB1 Cannabinoid Receptor Ligands Pp.631-640
Ganesh
A. Thakur, Spyros P. Nikas and Alexandros Makriyannis
CB2 Receptor Ligands Pp.641-649
J.W.
Huffman
CB1 and CB2 Cannabinoid
Receptor Binding Studies Based on Modeling and Mutagenesis Approaches Pp.651-658
Silvia
Ortega-Gutierrez and Maria L. Lopez-Rodriguez
Role of Endogenous Cannabinoids in Cognition
and Emotionality Pp.659-670
Carsten
T. Wotjak
The Role of Cannabinoid System on Immune
Modulation: Therapeutic Implications on CNS Inflammation Pp.671-675
Fernando
Correa, Leyre Mestre, Eduardo Molina-Holgado, Angel Arevalo-Martin, Fabian Docagne,
Eva Romero, Francisco Molina-Holgado, Jose Borrell and Carmen Guaza
General Reviews
Computational Chemistry as an Integral
Component of Lead Generation
Pp.677-683
Olivier
Roche and Wolfgang Guba
Anti-Cancer Drugs: Molecular Mechanisms of
Action Pp.685-695
Mauro
Cesar Isoldi, Maria Aparecida Visconti and Ana Maria de Lauro Castrucci
Abstracts
[Back to top] Editorial
Maria
L. Lopez-Rodriguez
Cannabinoids are
substances widely spread over a variety of organisms. Their effects have been
known and exploited by mankind since ancient times but only from an empirical
point of view. However, nowadays, leading advances in frontier disciplines
closely related such as molecular biology, synthetic chemistry and pharmacology
have led to the characterization of the endogenous cannabinoid system (ECS).
The identification
and cloning of two cannabinoid receptors, CB1 and CB2, in
the early 90´s as one of the main components of the ECS, facilitated the
entrance of cannabinoid research in the medicinal chemistry field, thus opening
new possibilities in the design and synthesis of new cannabinoid ligands with
controlled and predetermined affinities and activities.
The growing
evidences which point to the importance of ECS in the regulation of a
significant number of physiological processes is related with the fact that
alterations in this system are involved in the development of different
pathologies. This fact has converted the ECS into a promising therapeutic
target for the treatment of several disorders including some of the most
devastating neurodegenerative diseases such as Hungtinton´s chorea or multiple
sclerosis. These reasons widely justify the growing interest of many medicinal
chemistry groups in the ECS and more specifically, in the cannabinoid
receptors.
This issue
contains seven reviews contributed by leading experts which summarize the most
relevant findings in the field of cannabinoid receptors with the objective of
offering a current overview about the most important aspects in this highly
dynamic area.
Firstly, a general
overview of the ECS from a pharmacological and biochemical point of view is
presented. In this context, Drs. J. A. Ramos, S. González, O. Sagredo, M.
Gómez-Ruiz and J. Fernández-Ruiz offer a general perspective about the
pharmacology of the ECS and its function in the brain. Drs. I. Díaz-Laviada and
L. Ruiz-Llorente summarize the current knowledge of the signalling events
produced by cannabinoids from membrane receptors to downstream regulators.
Then, the ligands
of the cannabinoid receptors have been throughly reviewed. Drs. A. Makriyannis,
G.A. Thakur and S.P. Nikas reviewed the more recent advances in the development
of CB1 cannabinoid receptor ligands, whereas Dr. Huffman contributed
a complete overview about the most important aspects about CB2
ligands, including a discussion about structure-activity relationship studies.
In our review, we address the mutagenesis and molecular modelling approaches
developed during the last years and have allowed to get deeper insights about
the specific interactions responsible of binding and activation of cannabinoid
receptors.
Finally, two
particular involvements of cannabinoid receptors receive special attention. Dr.
C. Wotjak summarizes one of the most important implications of CB1
receptor in central nervous system regarding its interesting influence in
cognition and emotionality, and Drs. F. Correa, L. Mestre, E. Molina-Holgado,
A. Arévalo-Martín, F. Docagne, E. Romero, F. Molina-Holgado, J. Borrell and C.
Guaza cover the interesting issue of the effects of cannabinoids on immune
reactivity and on the regulation of neuroinflammatory processes asssociated
with chronic inflammatory demyelinating diseases such as multiple sclerosis.
I am very grateful
to all the above contributors for their excellent reviews and I hope readers
will enjoy this issue, which represents deep insight and excellent understanding
of the subject.
[Back to top] Therapeutic Potential of the Endocannabinoid
System in the Brain
Jose
Antonio Ramos, Sara Gonzalez, Onintza Sagredo, Maria Gomez-Ruiz and Javier
Fernandez-Ruiz
Cannabinoids have been
predominantly considered as the substances responsible of the psychoactive
properties of marijuana and other derivatives of Cannabis sativa.
However, these compounds are now being also considered for their therapeutic
potential, since the term “cannabinoid” includes much more compounds than those
present in Cannabis sativa derivatives. Among them, there are numerous
synthetic cannabinoids obtained by modifications from plant-derived
cannabinoids, but also from the compounds that behave as endogenous ligands for
the different cannabinoid receptor subtypes. Within the family of
“cannabinoid-related compounds”, one should also include some prototypes of
selective antagonists for these receptors, and also the recently developed
inhibitors of the mechanism of finalization of the biological action of
endocannabinoids (transporter + FAAH). All this boom of the cannabinoid
pharmacology has, therefore, an explanation in the recent discovery and
characterization of the endocannabinoid signaling system, which plays a
modulatory role mainly in the brain but also in the periphery. The objective of
the present article will be to review, from pharmacological and biochemical
points of view, the more recent advances in the study of the endocannabinoid
system and their functions in the brain, as well as their alterations in a
variety of pathologies and the proposed therapeutic benefits of novel
cannabinoid-related compounds that improve the pharmacokinetic and
pharmacodynamic properties of classic cannabinoids.
[Back to top] Signal Transduction Activated by Cannabinoid
Receptors
Ines
Diaz-Laviada and Lidia Ruiz-Llorente
Since the
discovery that cannabinoids exert biological actions through binding to
specific receptors, signal mechanisms triggered by these receptors have been
focus of extensive study. This review summarizes the current knowledge of the
signalling events produced by cannabinoids from membrane receptors to
downstream regulators. Two types of cannabinoid receptors have been identified
to date: CB1 and CB2 both belonging to the
heptahelichoidal receptor family but with different tissue distribution and
signalling mechanisms. Coupling to inhibitory guanine nucleotide-binding
protein and thus inhibition of adenylyl cyclase has been observed in both
receptors but other signal transduction pathways that are regulated or not by
these G proteins are differently activated upon ligand-receptor binding
including ion channels, sphingomyelin hydrolysis, ceramide generation,
phospholipases activation and downstream targets as MAP kinase cascade, PI3K,
FAK or NOS regulation.
Cannabinoids may
also act independently of CB1 or CB2 receptors. The
existence of new unidentified putative cannabinoid receptors has been claimed
by many investigators. Endocannabinoids activate vanilloid TRPV1 receptors that
may mediate some of the cannabinoid effects. Other actions of cannabinoids can
occur through non-receptor-mediated mechanisms.
[Back to top] CB1 Cannabinoid Receptor Ligands
Ganesh
A. Thakur, Spyros P. Nikas and Alexandros Makriyannis
The CB1 receptor
is expressed in the central nervous system and numerous other tissues including
heart, lung and uterus and has been recognized as an important therapeutic
target for pain, appetite modulation, glaucoma, multiple sclerosis and other
indications. An interesting feature of this GPCR is its ability to be activated
by a number of structurally different classes of compounds, thus, raising the
possibility of multiple activated forms of the receptor. Understanding of the
structure-activity relationships of cannabinergic ligands has paved the road
for the development of novel ligands exhibiting receptor subtype selectivity
and efficacy. This review highlights the important CB1 cannabinergic ligands
developed to date.
[Back to top] CB2 Receptor Ligands
J.W.
Huffman
The CB1
receptor is found principally in the central nervous system and is responsible
for the overt physiological effects of cannabinoids. In contrast, the CB2
receptor is expressed primarily in the immune system and is responsible for
few, if any, obvious behavioral effects. Although many cannabinoid receptor
ligands show little, or at best modest, selectivity for either receptor, a
number of synthetic compounds are known which have significant selectivity for
the CB2 receptor. These include cannabimimetic indoles, such as
1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015) and
1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpho-lino]ethyl)-5-methoxyindole
(L768242), both of which have good affinity for the CB2 receptor,
but weak affinity for the CB1 receptor. Efforts have been made to
develop structure-activity relationships (SAR) at CB2 for
cannabimimetic indoles, but with limited success. Several derivatives of
traditional dibenzopyran based cannabinoids have also been found to have
significant selectivity for the CB2 receptor. These include
1-methoxy-∆8-THC derivatives, 1-methoxy-∆8-THC-DMH
(L759633), 1-methoxy-∆9(11)-THC-DMH (L759656), and
1-methoxy-3-(1',1'-dimethylhexyl)-∆8-THC (JWH-229), plus a
number of 1-deoxy-∆8-THC analogues. In particular,
1-deoxy-3-(1',1'-dimethylbutyl)-∆8-THC (JWH-133) shows two
hundred-fold selectivity for the CB2 receptor. Very recently several
compounds belonging to other structural groups have also shown selectivity for
the CB2 receptor. This review will describe the current status of
the results of these studies and discuss the SAR for these classes of ligands.
[Back to top] CB1 and CB2 Cannabinoid
Receptor Binding Studies Based on Modeling and Mutagenesis Approaches
Silvia
Ortega-Gutierrez and Maria L. Lopez-Rodriguez
In absence of X
ray crystal structures of G-protein coupled receptors (GPCRs)-ligand complexes,
computer-aided molecular modeling together with site-directed mutagenesis
studies become of great importance in order to provide in-silico predictions
that facilitate the development of new ligands. In this context, the present
review addresses the application of these strategies to the CB1 and
CB2 cannabinoid receptors. The combination of these complementary
approaches represents a tool of considerable value which has allowed to
understand the specific ligand-receptor interactions.
[Back to top] Role of Endogenous Cannabinoids in Cognition
and Emotionality
Carsten
T. Wotjak
Novel
pharmacological tools and the generation of null-mutants enabled the
elucidation of the role of endocannabinoids in cognition and emotionality of
rats and mice. Endocannabinoids seem to limit memory retention, to facilitate
memory extinction and to ensure adequate coping with stressful situations. A
selective potentiation of these actions may lead to novel pharmacotherapies for
human anxiety disorders.
[Back to top] The Role of Cannabinoid System on Immune
Modulation: Therapeutic Implications on CNS Inflammation
Fernando
Correa, Leyre Mestre, Eduardo Molina-Holgado, Angel Arevalo-Martin, Fabian Docagne,
Eva Romero, Francisco Molina-Holgado, Jose Borrell and Carmen Guaza
There is a growing
amount of evidence suggesting that cannabinoids may be neuroprotective in CNS
inflammatory conditions. Advances in the understanding of the physiology and
pharmacology of the cannabinoid system have increased the interest of
cannabinoids as potential therapeutic targets. Cannabinoid receptors and their
endogenous ligands, the endocannabinoids, have been detected in cells of the
immune system, as well as in brain glial cells. In the present review it is
summarized the effects of cannabinoids on immune reactivity and on the
regulation of neuroinflammatory processes associated with brain disorders with
special attention to chronic inflammatory demyelinating diseases such as
multiple sclerosis.
[Back to top] Computational Chemistry as an Integral
Component of Lead Generation
Olivier
Roche and Wolfgang Guba
From library
shaping to ADME-Tox prediction via virtual screening, computational chemistry
is an integral component of Lead Generation. It provides a series of tools that
help focusing on compounds with a balanced pharmacodynamic and ADME-Tox profile
together with a high potential to optimize potency and selectivity.
[Back to top] Anti-Cancer Drugs: Molecular Mechanisms of
Action
Mauro
Cesar Isoldi, Maria Aparecida Visconti and Ana Maria de Lauro Castrucci
Genetic
alterations are responsible for all cancers. These mutations produce, in turn,
alterations in key proteins of certain signaling pathways. Amongst the best
known and studied alterations related to malignant transformations are those
which occur in Ras protein and p53. In most cases mutations in Ras and p53 lead
to the appearance of practically most malignant transformations. Mutated Ras
genes exist in approximately 20 to 30% of all human cancers. Ras proteins are
switches that regulate diverse functions such as cell proliferation,
differentiation and apoptosis. Normal p53 expression, also known as the “genome
guardian”, is a key molecule for suppressing cell proliferation.
The great
importance of these proteins rests on their intimacy with the events leading to
cell proliferation or death. The comprehension of the extent of transformation
on Ras and p53, and of the diverse biochemical pathways of intracellular
signaling, activated by them, is of extreme importance for the understanding of
malignant transformation, as well as its control, through the creation, for
example, of new drugs which contribute to the elimination of these cells.
To clarify the
consequences originated by transformed Ras, p53 and their biochemical
interlinks in the different intracellular pathways, besides the possible
intervening points and pharmacological controls presently used in combating
cancer, are the aims of this review.