An Update on Adenosine A2A Receptors as Drug Target in Parkinson's Disease (original) (raw)
Related papers
Pharmacology & Therapeutics, 2011
Several selective antagonists for adenosine A 2A receptors (A 2A R) 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 D 2 and adenosine A 2A receptors in the basal ganglia. At present it is believed that A 2A R 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 A 2A R antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized anti-parkinsonian drug therapy, namely the existence of receptor (hetero)dimers/oligomers of G protein-coupled receptors, a topic currently the focus of intense debate within the scientific community. Dopamine D 2 receptors (D 2 Rs) expressed in the striatum are known to form heteromers with A 2A adenosine receptors. Thus, the development of heteromer-specific A 2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs.
Targeting adenosine A 2A receptors in Parkinson's disease
Trends in Neurosciences, 2006
The adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5 and adenosine A1 receptors. Blockade of the adenosine A2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard ‘dopamine replacement’ treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.
New therapies for the treatment of Parkinson's disease: Adenosine A2A receptor antagonists
Life Sciences, 2005
The development of non-dopaminergic therapies for the treatment of Parkinson's disease (PD) has attracted much interest in recent years. Among new different classes of drugs, adenosine A2A receptor antagonists have emerged as best candidates. The present review will provide an updated summary of the results reported in literature concerning the effects of adenosine A2A antagonists in rodent and primate models of PD. These results show that A2A receptor antagonists improve motor deficits without inducing dyskinesia and counteract parkinsonian tremor. In progress clinical trials have shown that a low dose of l-DOPA plus KW-6002 produced symptomatic relief no different from that produced by an optimal dose of l-DOPA alone, whereas dyskinesias were reduced rendering this class of compounds particularly attractive.
Frontiers in neuroscience, 2017
Parkinson's disease (PD) is one of the most prevalent neurodegenerative disease displaying negative impacts on both the health and social ability of patients and considerable economical costs. The classical anti-parkinsonian drugs based in dopaminergic replacement are the standard treatment, but several motor side effects emerge during long-term use. This mini-review presents the rationale to several efforts from pre-clinical and clinical studies using adenosine receptor antagonists as a non-dopaminergic therapy. As several studies have indicated that the monotherapy with adenosine receptor antagonists reaches limited efficacy, the usage as a co-adjuvant appeared to be a promising strategy. The formulation of multi-targeted drugs, using adenosine receptor antagonists and other neurotransmitter systems than the dopaminergic one as targets, have been receiving attention since Parkinson's disease presents a complex biological impact. While pharmacological approaches to cure or ...
Adenosine A 2A receptors, dopamine D 2 receptors and their interactions in Parkinson's disease
Movement Disorders, 2007
Future therapies in Parkinson's disease may substantially build on the existence of intra-membrane receptor-receptor interactions in DA receptor containing heteromeric receptor complexes. The A 2A /D 2 heteromer is of substantial interest in view of its specific location in cortico-striatal glutamate terminals and in striato-pallidal GABA neurons. Antagonistic A 2A /D 2 receptor interactions in this heteromer demonstrated at the cellular level, and at the level of the striato-pallidal GABA neuron and at the network level made it possible to suggest A 2A antagonists as anti-parkinsonian drugs. The major mechanism is an enhancement of D 2 signaling leading to attenuation of hypokinesia, tremor, and rigidity in models of Parkinson's disease with inspiring results in two clinical trials. Other interactions are antagonism at the level of the adenylyl cyclase; heterologous sensitization at the A 2A activated adenylyl cyclase by persistent D 2 activation and a compensatory up-regulation of A 2A receptors in response to intermittent Levodopa treatment. An increased dominance of A 2A homomers over D 2 homomers and A 2A /D 2 heteromers after intermittent Levodopa treatment may therefore contribute to development of Levodopa induced dyskinesias and to the wearing off of the therapeutic actions of Levodopa giving additional therapeutic roles of A 2A antagonists. Their neuroprotective actions may involve an increase in the retrograde trophic signaling in the nigrostriatal DA system.
Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease
Journal of The Neurological Sciences, 2006
Preclinical evidence strongly indicate that adenosine A2A receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A2A receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A2A antagonist
Neurotoxicity Research, 2001
The most effective treatment of Parkinson's disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenyl-alanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term, effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A2A receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A2A antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-l,2,4-triazolo(1,5-c)pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Foslike-immunoreactivity in neurons of the lesioned striatum. Likewise, other A2A receptor antagonists such as (3,7-dimethyl-l-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-l,3-dipropyl-7-methylxanthine] (KF 17837) and [E-1,3-dietyl-8(3,4-dimethoxystyryl-7-methyl-3,7-dhydro-lH-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in nonhuman primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTPtreated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A2A receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A2A antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) (MPTP) model of PD. Adenosine A2A receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.
Adenosine A2Areceptor antagonist treatment of Parkinson’s disease
Neurology, 2003
Background: Observations in animal models suggest that A 2A antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A 2A receptormediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications. Methods: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A 2A antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design (40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale. Results: KW-6002 alone or in combination with a steady-state IV infusion of each patient's optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p Ͻ 0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone (p Ͻ 0.05). All cardinal parkinsonian signs improved, especially resting tremor. In addition, KW-6002 prolonged the efficacy half-time of levodopa by an average of 47 minutes (76%; p Ͻ 0.05). No medically important drug toxicity occurred. Conclusions: The results support the hypothesis that A 2A receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.
Neurochemistry International, 2013
The molecular interaction between adenosine A 2A and dopamine D 2 receptors (A 2A Rs and D 2 Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine-dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson's disease). While the effects of A 2A R challenge on D 2 R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D 2 R-mediated allosteric modulation of A 2A R binding when an A 2A R/D 2 R oligomer is established. Thus, we synthesized fluorescent A 2A R agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A 2A R binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D 2 R-mediated negative allosteric modulation on A 2A R agonist binding that was oligomerformation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A 2A R agonist binding. Overall, the here-developed methods were found valid to prospect the ability of drugs acting on D 2 Rs to modulate A 2A R binding, thus featuring as possible helpful tools for the preliminary selection of D 2 R-like candidate drugs in the management of Parkinson's disease.