New therapies for the treatment of Parkinson's disease: Adenosine A2A receptor antagonists (original) (raw)
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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.
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.
An Update on Adenosine A2A Receptors as Drug Target in Parkinson's Disease
CNS & Neurological Disorders - Drug Targets, 2011
Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiological functions of adenosine. In the central nervous system adenosine A 2A receptors (A 2A Rs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D 2 receptor (D 2 R). Furthermore, it is assumed that the formation of balanced A 2A R/D 2 R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A 2A R activation reduces the affinity of striatal D 2 R for dopamine and the blockade of A 2A R with specific antagonists facilitates function of the D 2 R. Thus, it may be postulated that A 2A R antagonists are pro-dopaminergic agents.
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.
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
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.
Annals of Neurology, 1998
's disease with L-dopa therapy leads to long-term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine AzA receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor disability in MPTP-treated common marmosets in a dose-dependent manner. However, KW-6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW-6002 induced little or no dyskinesia in MPTP-treated primates previously primed to exhibit dyskinesia by prior exposure to L-dopa. These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.
Progress in Neurobiology, 2007
Adenosine A 2A receptors have a unique cellular and regional distribution in the basal ganglia, being particularly concentrated in areas richly innervated by dopamine such as the caudate-putamen and the globus pallidus. Adenosine A 2A receptors are selectively located on striatopallidal neurons and are capable of forming functional heteromeric complexes with dopamine D 2 and metabotropic glutamate mGlu5 receptors. Based on the unique cellular and regional distribution of this receptor and in line with data showing that A 2A receptor antagonists improve motor symptoms in animal models of Parkinson's disease (PD) and in initial clinical trials, A 2A receptor antagonists have emerged as an attractive non-dopaminergic target to improve the motor deficits that characterize PD. Experimental data have also shown that A 2A receptor antagonists do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review provides an updated summary of results reported in the literature concerning the biochemical characteristics and basal ganglia distribution of A 2A receptors. We subsequently aim to examine the effects of adenosine A 2A antagonists in rodent and primate models of PD and of L-DOPA-induced dyskinesia. Finally, concluding remarks are made on post-mortem human brains and on the translation of adenosine A 2A receptor antagonists in the treatment of PD. #
European Neurology, 2012
The A 2A receptors' role in the pathophysiology of Parkinson's disease and DIMDs is evidenced by the upregulation of A 2A receptors in patients with Parkinson's disease and patients receiving long-term administration of dopamine blockers. Further, A 2A-receptor antagonists are effective in reversing parkinsonian motor deficits and extrapyramidal symptoms in animal models of Parkinson's disease and DIMDs. Understanding the role of A 2A-receptor antagonism in the pathophysiology of Parkinson's disease and DIMD has therapeutic implications.
Clinical Neuropharmacology, 2002
Blockade of the adenosine A 2A receptor potentiates the effects of levodopa in experimental animals and may offer a novel nondopaminergic target for drug therapy in Parkinson's disease (PD). Open-label trials suggest that the nonspecific adenosine antagonist theophylline improves parkinsonian symptoms and increases ON time in advanced patients with PD. In a double-blind, crossover, placebo-controlled trial, the authors investigated the ability of stable plasma levels of theophylline (between 10-20 µg/mL after 15 days of treatment) to modulate the long-duration response and the shortduration response of levodopa in 10 patients with PD. Although theophylline induced a longer duration of the effect of levodopa in all Unified Parkinson's Disease Rating Scale variables considered, including dyskinesias, maximal levodopa-induced improvement and the duration of the effect of levodopa did not differ significantly from placebo. Only the secondary variable "akinesia" showed a statistical tendency to a more prolonged beneficial response with theophylline during an acute levodopa test (short-duration response), and tremor worsened with theophylline during levodopa withdrawal (longduration response). No differences were observed during the subacute course of study medication added to levodopa. During this exploratory study, the effects of theophylline were not strong enough to potentiate clearly the antiparkinsonian action of levodopa or to increase ON time in patients with advanced PD.