Current Pharmaceutical Design - Volume 14, Issue 15, 2008

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, Ferre 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 D2 receptors 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.

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.

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.

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,

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 A2A receptors, 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.

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.

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.