Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson's disease

https://doi.org/10.1016/j.pharmthera.2011.07.004Get rights and content

Abstract

Several selective antagonists for adenosine A2A receptors (A2AR) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D2 and adenosine A2A receptors in the basal ganglia. At present it is believed that A2AR antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A2AR antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D2 receptors (D2Rs) expressed in the striatum are known to form heteromers with A2A adenosine receptors. Thus, the development of heteromer-specific A2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs.

Introduction

Adenosine receptors (AR) are members of the G protein-coupled receptor superfamily that have long been considered potential targets for the treatment of a variety of diseases, although to date adenosine (Adenocard® or Adenoscan®) is the only commercially available therapeutic drug acting on AR. Adenocard® is used clinically to revert paroxysmal supraventricular tachycardia, while Adenoscan® is also used for cardiac imaging due to its vasodilatory effects mediated by A2A receptors in blood vessels. Recently, the A2A-selective agonist regadenoson (Lexiscan®) was approved for the same indication. Despite the limited amount of clinically available compounds, it is still believed that drugs acting on adenosine receptors will be therapeutically useful. Indeed, five clinical trials are currently underway (phases I to III) to analyze the therapeutic potential of adenosine A2A receptor (A2AR) antagonists in the treatment of Parkinson's disease (PD). Novel adenosine antagonists may thus soon reach the market. The potential of these antagonists has been deduced from considerable investigation of the functional interactions between dopamine and adenosine receptors in the basal ganglia. The use of A2AR antagonists in Parkinson's disease (PD) is based on solid preclinical data showing that adenosinergic neuromodulation antagonizes dopaminergic neurotransmission in aspects relevant to motor control. Adenosine receptor antagonist-based therapy was initially founded on the hypothesis that preventing such antagonism could be useful in situations of dopamine deficit, such as occurs in Parkinson's disease. Notable efforts in medicinal chemistry have sought to develop A2AR antagonists. While the first approaches focused on xanthine derivatives, the current portfolio also includes highly promising non-xanthine drugs.

The use of A2AR antagonists in PD is not exclusively dependent on the outcome of the ongoing clinical trials with structurally distinct molecules. This is due to a shift in emphasis from simply improving the motor symptoms of the patients to developing strategies to prevent disease progression. Given the established efficacy of L-DOPA, and for ethical reasons, the main approach currently used in clinical trials involves the co-administration of A2AR antagonists with L-DOPA. The proposed advantage of this strategy is a reduction in the required dose of L-DOPA, with concomitant reductions in the associated side effects, consisting mainly of dyskinesias and progressive cognitive impairment. Preclinical findings also indicated potential neuroprotective effects of A2AR antagonists, an aspect highly relevant to PD treatment. Thus, in addition to improving motor symptoms when administered in combination with L-DOPA, A2AR antagonists may also exhibit true disease-modifying activity, delaying the progression of disease. Whether all A2AR antagonists being currently assayed in clinical trials are equally effective as co-adjuvants remains to be determined. However, the development of A2AR antagonists for the treatment of basal ganglia disorders should focus on optimizing both their effects against acute symptoms and their neuroprotective activity.

An additional and important consideration for the development of A2AR antagonists concerns the novel pharmacological effects derived from G protein-coupled receptor heteromerization. The existence of receptor heteromers has had a strong impact on the field of G protein-coupled receptors, raising important questions as to whether the real therapeutic targets are receptor monomers, homodimers or heteromers. A2AR and dopamine D2 receptors (D2R) were among the first G protein-coupled receptor heteromers identified, and have been detected in both transfected cells and brain striatal tissue (Soriano et al., 2009). Since receptor pharmacology is modified by heteromerization, the screening of given receptors in different heteromeric contexts should be incorporated into future drug discovery programs. Promising results have been obtained relating to A2AR heteromers (Orrú et al., 2011), which are implicated in Parkinson's and Huntington's diseases (HD), among others. As structurally distinct A2AR antagonists may exert differential effects on distinct A2AR-containing heteromers, different A2AR antagonists may be useful for the treatment of specific neurological disorders, depending on the heteromer preferentially targeted by the drug. In this review, we aim to address all these past-, present- and future aspects of the A2ARs and their antagonists.

Section snippets

Normal and abnormal basal ganglia function

PD is a basal ganglia-associated disorder that affects 1–2% of individuals over 60 years of age. The main symptoms of the disease are motor-related, including reduced spontaneous movement, akinesia (lack of movement), bradykinesia (slowness of movements), rigidity (due to increased muscular tone), as well as the characteristic resting tremor. The introduction of the dopamine precursor L-DOPA in the late 1960s, later followed by a number of dopamine agonists, has revolutionized the clinical

The role of A2A receptors (A2ARs) and A2AR heteromers in the modulation of striatal neurotransmission

The A2ARs are highly expressed in the basal ganglia and depend on Gs and other interacting proteins for correct transduction of their signals (Burgueño et al., 2003). The striatum is the anatomical region in mammals that most strongly expresses A2ARs, which are thought to fulfill an important role in the regulation of dopaminergic transmission in the basal ganglia (see Morelli et al., 2009). For instance, A2ARs co-localize postsynaptically with D2Rs in GABAergic striatopallidal enkephalinergic

Overview of important A2AR antagonists

Several review articles on adenosine receptor ligands in general (Fredholm et al., 2011, Müller and Jacobson, 2011a, Müller and Jacobson, 2011b) and A2AR antagonists in particular (Cristalli et al., 2009, Clementina and Giuseppe, 2010, Müller and Ferré, 2010, Shah and Hodgson, 2010) have appeared recently. The first adenosine receptor antagonists described in the literature were the plant alkaloids caffeine (1) and theophylline (2), which are characterized by their core xanthine structure (

Neuroprotection and Parkinson's disease — a general outlook

Replenishing the depleted dopamine stores with l-DOPA, its immediate precursor, thus mimicking dopamine-mediated neurotransmission, remains the basis of current PD treatment. Although this replacement therapy offers immediate and effective symptomatic relief, especially in the early stages of the disease, it does not have any influence on the underlying neurodegenerative processes. As a consequence, neuronal cell death progresses over time and is paralleled by a gradual loss of drug efficacy.

Rationale behind the screening of adenosine A2AR antagonists to improve motor symptoms in animal models and Parkinson's disease

The use of A2AR agonists has been associated with side effects, with 184 out of 334 patients (20 out of 170 in the placebo group) reporting adverse effects in the clinical trial NCT00863707 of regadenoson administered by intravenous bolus injection (0.4 mg/5 ml: available at http://clinicaltrials.gov), including headache, nausea, chest discomfort, dyspnea or dizziness. Nevertheless, A2AR agonists like regadenoson are safe and well tolerated when applied as pharmacological stress agents for

Effects of A2AR antagonists in parkinsonian patients: results from clinical trials

The development of new highly selective adenosine A2AR antagonists, and their encouraging antiparkinsonian responses in animal models of PD, has provided a rationale for clinical trials to evaluate the therapeutic potential and the safety of these agents in PD patients.

Targeting striatal pre- or postsynaptic A2ARs

The powerful capacity of presynaptic A2ARs to modulate striatal glutamate release was first demonstrated through in vivo microdialysis experiments (Popoli et al., 1995), which revealed that striatal perfusion of an A2AR agonist produced a very pronounced increase in the basal concentrations of extracellular striatal glutamate. Similarly, intrastriatal perfusion of an A2AR antagonist through a microdialysis probe significantly counteracted striatal glutamate release induced by cortical

Website list

www.biotie.com/en/recearch_and_development/central_nervous_system_disorders/syn115

http://www.clinicaltrials.gov/ct2/results?term=preladenant

www.clinicaltrials.gov/ct2/results?term=P04938

www.clinicaltrials.gov/ct2/results?term=P05664

www.clinicaltrials.gov/ct2/results?term=P07037

www.clinicaltrials.gov/ct2/results?term=P06153

www.istradefylline.com/fda.html

www.sigma-tau.it/eng/areediricerca.asp

www.vernalis.com/media-centre/latest-releases/2010-releases/584

//www.vernalis.com/media-centre/latest-releases/596

Acknowledgments

This research was funded within the frame of the Era-NET Neuron program by the following grants: SAF2008-03229-E (RF), SAF2009-07276 (RF) and SAF2008-03118-E (JLL) from the Spanish Ministry of Science and Innovation; 01EW0911 from the German Federal Ministry for Education and Research (BMBF) Germany (CM); and RC2008MinSal/Era-NET from the Italian Ministry of Health (MTA, AP). Support was also obtained through intramural funds of the National Institute in Drug Abuse (SF).

References (284)

  • S.A. Bura et al.

    A 2A adenosine receptor regulates glia proliferation and pain after peripheral nerve injury

    Pain

    (2008)
  • J. Burgueño et al.

    The adenosine A2A receptor interacts with the actin-binding protein alpha-actinin

    J Biol Chem

    (2003)
  • M. Canals et al.

    Adenosine A2A-dopamine D2 receptor-receptor heteromerization: Qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer

    J Biol Chem

    (2003)
  • V. Casadó et al.

    GPCR homomers and heteromers: A better choice as targets for drug development than GPCR monomers?

    Pharmacol Ther

    (2009)
  • J.L. Cavalcante et al.

    Regadenoson is a safe and well-tolerated pharmacological stress agent for myocardial perfusion imaging in post-heart transplant patients

    J Nucl Cardiol

    (2011)
  • J.F. Chen et al.

    Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation

    Prog Neurobiol

    (2007)
  • L.E. Collins et al.

    Interactions between adenosine and dopamine receptor antagonists with different selectivity profiles: Effects on locomotor activity

    Behav Brain Res

    (2010)
  • M. Correa et al.

    The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: Possible relevance to parkinsonism

    Behav Brain Res

    (2004)
  • A.R. Crossman

    Primate models of dyskinesia: The experimental approach to the study of basal ganglia-related involuntary movement disorders

    Neuroscience

    (1987)
  • J.A. DeLeo et al.

    The role of neuroinflammation and neuroimmune activation in persistent pain

    Pain

    (2001)
  • M. DeLong

    Primate models of movement disorders of basal ganglia origin

    Trends Neurosci

    (1990)
  • S. Factor et al.

    A long-term study of istradefylline in subjects with fluctuating Parkinson's disease

    Parkinsonism Relat Disord

    (2010)
  • B.A. Faucheux et al.

    Blood vessels change in the mesencephalon of patients with Parkinson's disease

    Lancet

    (1999)
  • S. Fenu et al.

    Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats

    Eur J Pharmacol

    (1997)
  • H.H. Fernandez et al.

    Istradefylline as monotherapy for Parkinson disease: Results of the 6002-US-051 trial

    Parkinsonism Relat Disord

    (2010)
  • S. Ferré et al.

    Functional relevance of neurotransmitter receptor heteromers in the central nervous system

    Trends Neurosci

    (2007)
  • S. Ferré et al.

    Looking for the role of cannabinoid receptor heteromers in striatal function

    Neuropharmacol

    (2009)
  • J.S. Fowler et al.

    Age-related increases in brain monoamine oxidase B in living healthy human subjects

    Neurobiol Aging

    (1997)
  • B.B. Fredholm et al.

    Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells

    Biochem Pharmacol

    (2001)
  • C.V. Gomes et al.

    Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration

    Biochim Biophys Acta

    (2011)
  • L. Halldner et al.

    Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist

    Eur J Pharmacol

    (2000)
  • G. Hasko et al.

    Adenosine receptor signaling in the brain immune system

    Trends Pharmacol Sci

    (2005)
  • R.A. Hauser et al.

    Preladenant in patients with Parkinson's disease and motor fluctuations: A phase 2, double-blind, randomised trial

    Lancet Neurol

    (2011)
  • N.J. Abbott

    Inflammatory mediators and modulation of blood–brain barrier permeability

    Cell Mol Neurobiol

    (2000)
  • N.J. Abbott et al.

    Control of brain endothelial permeability

    Cerebrovasc Brain Metab Rev

    (1991)
  • M. Andersson et al.

    Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons

    J Neurosci

    (2005)
  • E. Angulo et al.

    A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation

    Brain Pathol

    (2003)
  • M.T. Armentero et al.

    Peripheral expression of key regulatory kinases in Alzheimer's disease and Parkinson's disease

    Neurobiol Aging

    (2010)
  • M.J. Arnaud

    Pharmacokinetics and metabolism of natural methylxanthines in animal and man

    Handb Exp Pharmacol

    (2011)
  • A. Ascherio et al.

    Prospective study of caffeine consumption and risk of Parkinson's disease in men and women

    Ann Neurol

    (2001)
  • K. Azdad et al.

    Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A-D2 receptor heteromerization

    Neuropsychopharmacology

    (2009)
  • W. Bara-Jimenez et al.

    Adenosine A(2A) receptor antagonist treatment of Parkinson's disease

    Neurology

    (2003)
  • P. Bezzi et al.

    CXCR4-activated astrocyte glutamate release via TNFalpha: Amplification by microglia triggers neurotoxicity

    Nat Neurosci

    (2001)
  • A. Bilkei-Gorzo et al.

    Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia

    Naunyn Schmiedeberg's Arch Pharmacol

    (2008)
  • K.J. Black et al.

    A randomized, double-blind, placebo-controlled cross-over trial of the adenosine 2a antagonist SYN115 in Parkinson disease

  • K.J. Black et al.

    Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson's disease

    J Neurosci

    (2010)
  • F. Blandini

    An update on the potential role of excitotoxicity in the pathogenesis of Parkinson's disease

    Funct Neurol

    (2010)
  • F. Blandini et al.

    Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson's disease

    Ann Neurol

    (2001)
  • M.L. Block et al.

    Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms

    Nat Rev Neurosci

    (2007)
  • D. Blum et al.

    A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions: Implications for the neuroprotective potential of A2A antagonists

    J Neurosci

    (2003)
  • Cited by (0)

    1

    These authors contributed equally to the present work.

    View full text