Blocking Striatal Adenosine A2A Receptors: A New Strategy for Basal Ganglia Disorders (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.
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.
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.
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.
Striatal Pre-and Postsynaptic Profile of Adenosine A2A Receptor Antagonists
PloS one, 2011
Striatal adenosine A 2A receptors (A 2A Rs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D 2 receptors (D 2 Rs). A 2A Rs are also localized presynaptically in corticostriatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A 1 receptors (A 1 Rs). It has been hypothesized that postsynaptic A 2A R antagonists should be useful in Parkinson's disease, while presynaptic A 2A R antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessivecompulsive disorders and drug addiction. The aim or this work was to determine whether selective A 2A R antagonists may be subdivided according to a preferential pre-versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre-and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre-and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A 2A R-D 2 R and A 1 R-A 2A R heteromers to determine possible differences in the affinity of these compounds for different A 2A R heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A 2A R when co-expressed with D 2 R than with A 1 R. KW-6002 showed the best relative affinity for A 2A R coexpressed with D 2 R than co-expressed with A 1 R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre-and postsynaptic profile. On the basis of their preferential pre-versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively. Citation: Orru M, Bakešová J, Brugarolas M, Quiroz C, Beaumont V, et al. (2011) Striatal Pre-and Postsynaptic Profile of Adenosine A 2A Receptor Antagonists. PLoS ONE 6(1): e16088.
ST 1535: a preferential A2A adenosine receptor antagonist
The International Journal of Neuropsychopharmacology, 2005
Antagonism of the A 2A adenosine function has proved beneficial in the treatment of Parkinson's disease, in that it increases L-dopa therapeutical effects without concomitant worsening of its side-effects. In this paper we describe a preferential A 2A adenosine antagonist, ST 1535, with long-lasting pharmacodynamic effects. It competitively antagonizes the effects of the A 2A adenosine agonist NECA on cAMP in cells cloned with the human A 2A adenosine receptor (IC 50 =353¡30 nM), and the effects of the A 1 adenosine agonist CHA on cAMP in cells cloned with the human A 1 adenosine receptor (IC 50 =510¡38 nM). ST 1535, at oral doses of 5 and 10 mg/kg, antagonizes catalepsy induced by intracerebroventricular administration of the A 2A adenosine agonist CGS 21680 (10 mg/5 ml) in mice. At oral doses ranging between 5 and 20 mg/kg, ST 1535 induces hypermotility and antagonizes haloperidol-induced catalepsy in mice up to 7 h. Oral ST 1535, at 1.25 and 2.5 mg/kg, potentiates L-dopa effects in reducing haloperidol-induced catalepsy. ST 1535 represents a potential new compound, with long-lasting activity, for the treatment of Parkinson's disease.
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.