Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson's disease
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
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).
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These authors contributed equally to the present work.