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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] [Purchase
Article]
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] [Purchase
Article]
Modulation of Ischemic Brain Injury and Neuroinflammation
by Adenosine A2A Receptors
Pp. 1490-1499
J-F. Chen and F. Pedata
[Abstract] [Purchase
Article]
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] [Purchase
Article]
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] [Purchase
Article]
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] [Purchase
Article]
Abstracts
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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
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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]
[Purchase
Article]
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]
[Purchase
Article]
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]
[Purchase
Article]
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]
[Purchase
Article]
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]
[Purchase
Article]
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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