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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 15 2008
Contents
Regulation of Brain Functions by Adenosine A2A
Receptors: Implication for Therapeutics
Executive Editor: Patrizia Popoli
Editorial: Pp. 1466-1467
An Update on Adenosine A2A-Dopamine
D2 Receptor Interactions: Implications
for the Function of G Protein-Coupled Receptors Pp.
1468-1474
S. Ferré, C. Quiroz, A.S. Woods, R. Cunha, P. Popoli,
F. Ciruela, C. Lluis, R. Franco, K. Azdad and S. N.
Schiffmann
[Abstract]
Adenosine A2A Receptor
Antagonists and Parkinson’s Disease: State of the Art
and Future Directions Pp. 1475-1489
N. Simola, M. Morelli and A. Pinna
[Abstract]
Modulation of Ischemic Brain Injury and Neuroinflammation
by Adenosine A2A Receptors
Pp. 1490-1499
J-F. Chen and F. Pedata
[Abstract]
A Critical Evaluation of Adenosine A2A
Receptors as Potentially “Druggable” Targets in
Huntington’s Disease Pp. 1500-1511
P. Popoli, D. Blum, M.R. Domenici, S. Burnouf and
Y. Chern
[Abstract]
Potential Therapeutic Interest of Adenosine A2A
Receptors in Psychiatric Disordersb Pp. 1512-1524
R.A. Cunha, S. Ferré, J-M. Vaugeois and
J-F. Chen
[Abstract]
A2A Adenosine Receptor
and Its Modulators: Overview on a Druggable GPCR and on Structure-Activity
Relationship Analysis and Binding Requirements of Agonists and
Antagonists Pp. 1525-1552
G. Cristalli, C. Lambertucci, G. Marucci, R. Volpini
and D. Dal Ben
[Abstract]
Abstracts
[Back to top]
Editorial: Regulation of Brain Functions by
A2A Receptors: Implication for Therapeutics
Adenosine is an endogenous modulator which regulates many Central
Nervous System (CNS) functions and which activities are mediated
by the binding to four distinct G-protein-coupled receptors:
the A1, A2A,
A2B, and A3
adenosine receptor subtypes.
In the last few years adenosine A2A
receptors have been shown to play a significant role in different
physiological and pathological processes in the brain. The aim
of this issue is to review and critically discuss the evidence
supporting adenosine A2A receptors
as possible therapeutic targets for CNS disorders.
It is my genuine belief that this topic, albeit controversial,
is actually worth exploring and debating, and thus I’m
particularly grateful to Prof. Banks for inviting me to edit
this issue. I’m also very grateful to all the contributors
(most of whom have actually pioneered the field), who accepted
to share their thoughts and experience in this fascinating topic.
On their whole, the articles of this issue very nicely and comprehensively
summarize the state of the art and outline the many aspects
which still need to be clarified. From these articles it becomes
clear that, despite the many controversial evidence and the
current “druggability” problems, adenosine A2A
receptors continue to represent promising drug targets for CNS
diseases. I wish that this issue of Current Pharmaceutical Design
will further stimulate the research in this field.
In neurons, the highest expression of the adenosine A2A
receptors is found in the basal ganglia, in particular in the
corpus striatum, which is involved in the control and learning
of complex motor activities. The discovery of the colocalization
of dopamine D2 and adenosine
A2A receptors in a subset of
striatal neurons has provided an anatomical basis to the functional
antagonism between adenosine and dopamine in the basal ganglia.
In their review, Ferré et al. [1] show that
the A2A-D2
receptor interactions provide an example of the capabilities
of information processing by just two different G protein-coupled
receptors. They report the evidence for the coexistence of two
reciprocal antagonistic interactions between A2A
and D2receptors in the same
neurons (the GABAergic enkephalinergic neurons) but, at the
same time, they show that under particular conditions (such
as chronic treatment with addictive drugs), a synergistic A2A-D2
receptor interaction can also be demonstrated. The analysis
of A2-D2
receptor interactions can thus have important implications for
the pathophysiology and treatment of basal ganglia disorders
and drug addiction.
Adenosine A2A receptor antagonists
currently constitute an attractive non-dopaminergic option for
the treatment of Parkinson's disease (PD). The highly enriched
distribution of adenosine A2A
receptors in striatopallidal neurons, and their ability to form
functional heteromeric complexes with dopamine D2
and metabotropic glutamate mGlu5 receptors, render A2A
receptor antagonists of particular interest in the modulation
of motor behaviour, whilst at the same time displaying a low
predisposition to inducing non-motor side effects. Furthermore,
adenosine A2A receptor antagonists
appear to exert a marked efficacy on PD tremor and in reducing
the progress of underlying neurodegeneration and maladaptive
neuroplasticity that complicates standard dopamine replacement
treatments in PD. Finally, recent evidence has illustrated an
improvement of cognitive function as well as enhancement of
attention in rodents following administration of A2A
receptor antagonists. The state of the art and the future directions
in the field of A2A receptor
antagonists as antiparkinsonian drugs is comprehensively covered
by the review of Simola et al. [2] in this issue. Their
article examines preclinical studies as well as reports from
clinical trials, in order to provide a comprehensive review
of the evidence suggesting that this class of drugs may represent
an advance in the treatment of PD.
Recently, the A2A receptor
has emerged as an attractive therapeutic target for modulating
brain ischaemia. The evidence we have to date indicates that
both adenosine and A2A antagonists
are neuroprotective in ischaemic brain injury. In their review,
Chen and Pedata [3] propose that, from drug development perspective,
administering A2A antagonists
in association with inhibitors of adenosine kinase may represent
a novel strategy for treating stroke. Their article also summarizes
the experimental evidence for A2AR
modulation of glial function as possible contribution to the
modulation of brain injury and points out the fact that, in
contrast to the generally held view that the A2AR
exerts predominantly anti-inflammatory effects (based upon studies
in peripheral organs), the A2AR
modulation of neuroinflammation may differentially affect the
outcome of brain injury, depending on the nature of brain insults.
A2A receptors have also been
hypothesized to play a role in Huntington ‘s disease (HD),
a dominantly inherited neurodegenerative disorder. This hypothesis
was originally based on the observation that the GABAergic enkephalin
neurons of the basal ganglia, which show the highest levels
of expression of adenosine A2A
receptors, are the most vulnerable in HD. In agreement, changes
in A2A receptor expression
and signalling have been reported in various experimental models
of HD. The interpretation of the functional significance of
the aberrant A2A receptor phenotype
in HD mice is however complicated by the conflicting data so
far reported on the potential neuroprotective and neurodegenerative
effects of these receptors in the brain, with some data suggesting
a potential pathogenetic role and some other data suggesting
activation of trophic or protective pathways in neurons. The
review by myself et al. [4] in this issue critically
evaluates whether adenosine A2Areceptors
may represent a suitable target to develop drugs against HD.
The review by Cunha et al. [5] deals with the role
of A2A receptors as a normalizing
device promoting adequate adaptive responses in neuronal circuits,
which makes A2A receptors a
particularly attractive target to manage psychiatric disorders.
Furthermore, A2Areceptors also
control glia function and brain metabolic adaptation, two other
emerging mechanisms to understand abnormal processing of mood,
and A2A receptors are an important
player in controlling the demise of neurodegeneration, considered
an amplificatory loop in psychiatric disorders. Current data
only provide an indirect confirmation of this putative role
of A2A receptors, based on
the effects of caffeine (an antagonist of both A1
and A2A receptors) in psychiatric
disorders. However, the introduction of A2A
receptors in clinics as anti-parkinsonian agents is hoped to
bolster our knowledge on the role of A2A
receptors in mood disorders in the near future.
The last article, from Cristalli et al. [6], deals
with the medicinal chemistry of adenosine receptors. Despite
problems such as side effects due to the ubiquity of the receptors,
low brain penetration, short half-life of compounds, lack of
effects, and species differences in the affinity of ligands,
adenosine receptors continue to represent promising drug targets.
In particular, the A2A receptor
has proved to be a promising pharmacological target for small
synthetic ligands. Furthermore, the information coming from
bioinformatics and molecular modelling studies for the A2A
receptor has made easier the understanding of ligand-target
interaction and the rational design of agonists and antagonists
for this subtype. In this article Cristalli et al.
show an overview of the most significant steps and progresses
in developing A2A adenosine
receptor agonists and antagonists.
References
[1] Ferré S, Quiroz C, Woods A S, Cunha R, Popoli P,
Ciruela F, Lluis C, Franco R, Azdad K, Schiffmann SN. An Update
on Adenosine A2A-Dopamine D2
receptor interactions. Implications for the Function of G Protein-Coupled
Receptors. Curr Pharm Des 2008; 14(15): 1468-1474.
[2] Simola N, Pinna A, Morelli M. A2A
receptor antagonists and Parkinson's Disease: state of the art
and future directions. Curr Pharm Des 2008; 14(15): 1475-1489.
[3] Chen J-F, Pedata F. Modulation of ischemic brain injury
and neuroinflammation by adenosine A2A
receptors. Curr Pharm Des 2008; 14(15): 1490-1499.
[4] Popoli P, Blum D, Domenici MR, Burnouf S, Y Chern. A critical
evaluation of adenosine A2A
receptors as “druggable” targets in Huntington’s
disease. Curr Pharm Des 2008; 14(15): 1500.1511.
[5] Cunha R, Ferré S, Vaugeois JM, Chen JF. Potential
therapeutic interest of A2A
receptors in psychiatric disorders. Curr Pharm Des 2008; 14(15):
1512-1524.
[6] Cristalli G, Lambertucci C, Marucci G, Volpini R, Dal Ben
D. A2A Adenosine receptor and
its modulators: overview on a druggable GPCR and on structure-activity
relationship analysis and binding requirements of agonists and
antagonists. Curr Pharm Des 2008; 14(15): 1525-1552.
Patrizia Popoli
Section of Central Nervous System Pharmacology
Department of Therapeutic Research and Medicines Evaluation
Istituto Superiore di Sanità
Rome
Italy
E-mail: patrizia.popoli@iss.it
[Back to top]
An Update on Adenosine A2A-Dopamine
D2 Receptor Interactions: Implications
for the Function of G Protein-Coupled Receptors
S. Ferré, C. Quiroz, A.S. Woods, R. Cunha, P. Popoli,
F. Ciruela, C. Lluis, R. Franco, K. Azdad and S. N.
Schiffmann
Adenosine A2A-dopamine
D2 receptor interactions play
a very important role in striatal function. A2A-D2
receptor interactions provide an example of the capabilities
of information processing by just two different G protein-coupled
receptors. Thus, there is evidence for the coexistence of two
reciprocal antagonistic interactions between A2A
and D2 receptors in the same
neurons, the GABAergic enkephalinergic neurons. An antagonistic
A2A-D2
intramembrane receptor interaction, which depends on A2A-D2
receptor heteromerization and Gq/11-PLC
signaling, modulates neuronal excitability and neurotransmitter
release. On the other hand, an antagonistic A2A-D2
receptor interaction at the adenylyl-cyclase level, which depends
on Gs/olf- and Gi/o-
type V adenylyl-cyclase signaling, modulates protein phosphorylation
and gene expression. Finally, under conditions of upregulation
of an activator of G protein signaling (AGS3), such as during
chronic treatment with addictive drugs, a synergistic A2A-D2
receptor interaction can also be demonstrated. AGS3 facilitates
a synergistic interaction between Gs/olf
- and Gi/o-coupled receptors
on the activation of types II/IV adenylyl cyclase, leading to
a paradoxical increase in protein phosphorylation and gene expression
upon co-activation of A2A and
D2 receptors. The analysis
of A2-D2
receptor interactions will have implications for the pathophysiology
and treatment of basal ganglia disorders and drug addiction.
[Back to top]
Adenosine A2A Receptor
Antagonists and Parkinson’s Disease: State of the Art
and Future Directions
N. Simola, M. Morelli and A. Pinna
Adenosine A2A receptors
present in the central nervous system have been implicated in
the modulation of motor functions. Accordingly, adenosine A2A
receptor antagonists currently constitute an attractive non-dopaminergic
option for use in the treatment of Parkinson's disease (PD).
The highly enriched distributions of adenosine A2A
receptors in striatopallidal neurons, and their ability to form
functional heteromeric complexes with dopamine D2
and metabotropic glutamate mGlu5 receptors, render A2A
receptor antagonists of particular interest in the modulation
of motor behavior, whilst at the same time displaying a low
predisposition to inducing non-motor side effects. Furthermore,
adenosine A2A receptor antagonists
appear to exert a marked efficacy on PD tremor and in reducing
the progress of underlying neurodegeneration and maladaptive
neuroplasticity that complicates standard dopamine replacement
treatments in PD. Finally, recent evidence has illustrated an
improvement of cognitive function as well as enhancement of
attention in rodents following administration of A2A
receptor antagonists. This article is aimed at examining preclinical
studies describing these findings as well as reports from clinical
trials, in order to provide a comprehensive review of the evidence
suggesting that this class of drugs may represent an advance
in the treatment of PD.
[Back to top]
Modulation of Ischemic Brain Injury and Neuroinflammation
by Adenosine A2A Receptors
J-F. Chen and F. Pedata
Over the past 5 years, the adenosine A2A
receptor (A2AR) is emerging as an attractive therapeutic target
for modulating brain injury in a variety of animal models of
neurological disorders including stroke. The evidence we have
to date indicates that both adenosine and A2A
antagonists are neuroprotective in ischaemic brain injury. From
drug development perspective, administering A2A
antagonists in association with inhibitors of adenosine kinase
may represent a novel strategy for treating stroke. Despite
the well-documented neuroprotection by A2AR
antagonists, the mechanism by which A2ARs
affect brain injury remains largely unknown. In this section,
we also summarize the experimental evidence for A2AR
modulation of glial function as possible contribution to the
modulation of brain injury. In vitro and in vivo
studies reveal that in response to local neuroinflammation following
brain insults, time-dependent, inflammatory signal-mediated
induction of the A2AR in glial
cells (particularly microglial cells) make this cell type particularly
sensitive to A2AR modulation
of brain injury. Furthermore, in contrast to the generally held
view that the A2AR exerts predominantly
anti-inflammatory effects (based upon studies in peripheral
organs), the A2AR modulation
of neuroinflammation may differentially affect the outcome of
brain injury, depending on the nature of brain insults. Thus,
in association with their ability to reduce brain injury, inactivation
of the A2AR in most models
and activation of A2AR in some
cases have been shown to attenuate brain inflammation through
control of the proliferation and production of proinflammatory
cytokines,
[Back to top]
A Critical Evaluation of Adenosine A2A
Receptors as Potentially “Druggable” Targets in
Huntington’s Disease
P. Popoli, D. Blum, M.R. Domenici, S. Burnouf and
Y. Chern
Huntington’s disease (HD) is a dominantly inherited
neurodegenerative disorder caused by the expansion of a polymorphic
CAG trinucleotide repeat encoding a poly-glutamine tract within
the Huntingtin protein. GABAergic enkephalin neurons of the
basal ganglia, which show the highest levels of expression of
adenosine A2Areceptors, are
the most vulnerable in HD. Such a selective neuronal vulnerability,
which occurs despite ubiquitous expression of mutant and normal
Huntingtin, has suggested that adenosine A2A
receptors might play a pathogenetic role in HD. In agreement,
changes in A2A receptor expression
and signaling have been reported in various experimental models
of HD. The interpretation of the functional significance of
the aberrant A2A receptor phenotype
in HD mice is however complicated by the conflicting data so
far reported on the potential neuroprotective and neurodegenerative
effects of these receptors in the brain, with some data suggesting
a potential pathogenetic role and some other data suggesting
activation of trophic or protective pathways in neurons. The
same complex profile has emerged in experimental models of HD,
in which both A2A receptor
agonists and antagonists have shown beneficial effects. The
main aim of this review is to critically evaluate whether adenosine
A2A receptors may represent
a suitable target to develop drugs against HD.
[Back to top]
Potential Therapeutic Interest of Adenosine A2A
Receptors in Psychiatric Disorders
R.A. Cunha, S. Ferré, J-M. Vaugeois and
J-F. Chen
The interest on targeting adenosine A2A
receptors in the realm of psychiatric diseases first arose based
on their tight physical and functional interaction with dopamine
D2 receptors. However, the
role of central A2A receptors
is now viewed as much broader than just controlling D2
receptor function. Thus, there is currently a major interest
in the ability of A2A receptors
to control synaptic plasticity at glutamatergic synapses. This
is due to a combined ability of A2A
receptors to facilitate the release of glutamate and the activation
of NMDA receptors. Therefore, A2A
receptors are now conceived as a normalizing device promoting
adequate adaptive responses in neuronal circuits, a role similar
to that fulfilled, in essence, by dopamine. This makes A2A
receptors particularly attractive targets to manage psychiatric
disorders since adenosine may act as go-between glutamate and
dopamine, two of the key players in mood processing. Furthermore,
A2A receptors also control
glia function and brain metabolic adaptation, two other emerging
mechanisms to understand abnormal processing of mood, and A2A
receptors are important players in controlling the demise of
neurodegeneration, considered an amplificatory loop in psychiatric
disorders. Current data only provide an indirect confirmation
of this putative role of A2A
receptors, based on the effects of caffeine (an antagonist of
both A1 and A2A
receptors) in psychiatric disorders. However, the introduction
of A2A receptors antagonists
in clinics as anti-parkinsonian agents is hoped to bolster our
knowledge on the role of A2A
receptors in mood disorders in the near future.
[Back to top]
A2A Adenosine Receptor
and Its Modulators: Overview on a Druggable GPCR and on Structure-Activity
Relationship Analysis and Binding Requirements of Agonists and
Antagonists
G. Cristalli, C. Lambertucci, G. Marucci, R. Volpini
and D. Dal Ben
Since the discovery of the biological effects of adenosine,
the development of potent and selective agonists and antagonists
of adenosine receptors has been the subject of medicinal chemistry
research for several decades, even if their clinical evaluation
has been discontinued. Main problems include side effects due
to the ubiquity of the receptors and the possibility of side
effects, or to low brain penetration (in particular for the
targeting of CNS diseases), short half-life of compounds, lack
of effects. Furthermore, species differences in the affinity
of ligands make difficult preclinical testing in animal models.
Nevertheless, adenosine receptors continue to represent promising
drug targets. A2A receptor
has proved to be a promising pharmacological target for small
synthetic ligands, and while A2A
agonists are undergoing clinical trials for myocardial perfusion
imaging and as anti-inflammatory agents, A2A
antagonists represent an attractive field of research to discover
new drugs for the treatment of neurodegenerative disorders,
such as Parkinson's disease. Furthermore, the information coming
from bioinformatics and molecular modeling studies for the A2A
receptor has made easier the understanding of ligand-target
interaction and the rational design of agonists and antagonists
for this subtype. The aim of this review is to show an overview
of the most significant steps and progresses in developing A2A
adenosine receptor agonists and antagonists.
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