Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine A2A receptor antagonist istradefylline has been approved this year for manufacturing and marketing in Japan. We, therefore, did this meta-analysis to systematically assess the efficacy and safety of istradefylline as augmentation to levodopa in patients with Parkinson's disease (PD). We systematically review the relative randomized controlled trials (RCTs) up to March 2014, which compared istradefylline to placebo for the short course of treatment for PD in adults. The primary outcome was daily OFF time and secondary outcome was UPDRS Part III score (on state). Data were obtained from seven RCTs, including 2205 patients. Compared to placebo on primary and secondary outcome, istradefylline group both showed significant reductions (WMD -0.60, p = 0.0001; WMD -1.07, p = 0.002). Subgroup analysis suggested that istradefylline 20, 40, and 60 mg/day in both group showed significant reductions on the two outcomes. Based on these results, Istradefylline could be an efficacy and safety augmentation drug added on to levodopa or other existing anti-Parkinsonian therapies. Limited by the number of studies, future large-scale studies are needed to verify these results, assess the long-term effect of istradefylline and the effect of istradefylline as monotherapy, and find the most effective dose of istradefylline.
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PMID:Efficacy of adenosine A2A receptor antagonist istradefylline as augmentation for Parkinson's disease: a meta-analysis of randomized controlled trials. 2509 4

Adenosine A2A receptor antagonists represent a new way forward in the symptomatic treatment of Parkinson's disease (PD) through a non-dopaminergic mechanism. As a class, adenosine A2A antagonists are effective in reversing motor deficits in haloperidol-treated rodents, 6-OHDA-lesioned rats, and MPTP-treated primates when combined with low doses of l-dopa or dopamine agonist drugs. Importantly, they improve motor function without worsening dyskinesia and they may prevent the onset of involuntary movements. Adenosine A2A receptor antagonists are active in animal models of reduced cognition, anxiety, and depression and so this drug class may also be effective in controlling the neuropsychiatric components of nonmotor symptoms in PD. Preclinical evidence has shown that A2A antagonists can prevent neuronal loss in experimental models of PD and their disease modifying activity needs to be explored in man. Importantly, a number of A2A antagonists have been studied in PD in clinical trial for their effects on motor function. So far, little evidence has emerged of an effect of monotherapy with adenosine antagonists in early PD. However, in later stage, patient populations already treated with dopaminergic drugs but exhibiting "wearing off," adenosine antagonists have been demonstrated to reduce "off" time without increasing troublesome dyskinesia in phase IIB trials. However, in larger phase III evaluations, a consistent significant decrease in "off" time has proved more difficult to demonstrate-due in part to trial conduct. So far, only istradefylline has completed phase III development and it is now marketed for the treatment of PD. Adenosine A2A antagonists are the first non-dopaminergic approach to the treatment of PD to appear in the recent era. They represent a novel way of approaching therapy that will provide additional benefit to that achieved with dopaminergic medication, while avoiding common side effects and may in addition, improve some nonmotor symptoms of PD that are currently poorly treated.
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PMID:An overview of adenosine A2A receptor antagonists in Parkinson's disease. 2517 61

Adenosine A2A receptor antagonists are classified to be a recent new therapeutic strategy for the symptomatic treatment of Parkinson's disease, a hypokinetic movement disorder. First, this chapter addresses how adenosine A2A receptors are involved with brain motor control via the basal ganglia-thalamocortical circuit, considering anatomical and ultrastructural localization of the receptor in critical areas/neurons of the circuit. Then, based on the understanding of the functional significance of the receptor in the circuit, the mode of action of adenosine A2A receptor antagonists is explained by dynamism of the circuit and possible cellular mechanisms, highlighting the importance of the pathophysiological difference proposed between normal and disease state.
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PMID:Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson's disease. 2517 62

Dopamine replacement therapy using the dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), with a peripheral dopa decarboxylase inhibitor is the most effective treatment currently available for the symptoms of Parkinson's disease (PD). However, the long-term use of dopaminergic therapies for PD is often limited by the development of motor response complications, such as dyskinesia. Adenosine A2A receptors are a promising nondopaminergic target for the treatment of PD. The treatment of motor response complications involves combinations of regular and controlled release L-DOPA, perhaps with the addition of a COMT inhibitor or the use of a longer-acting dopamine agonist. However, when dyskinesia is already established, the increase in dopaminergic load produced by the addition of a dopamine agonist can result in an increase in the severity and duration of dyskinesia. Currently, there are no well-tolerated antidyskinesia agents available. Amantadine, which may exert its effects through the inhibition of N-methyl-D-aspartate (NMDA) receptors, shows some effects on established dyskinesia. Dyskinesia has a negative impact on the quality of life of patients, sometimes being more disabling than PD itself. Although some patients prefer experiencing dyskinesia than being in the OFF state and unable to move, alternative, more effective therapies are still required for severe disabling dyskinesia to afford patients an improved quality of life while in the ON state. The mechanisms causing and maintaining the dyskinesia have not been clarified. The application of a nondopaminergic approach to modify the basal ganglial activity would be helpful to better understand and treat dyskinesia. The use of an adenosine A2A receptor may provide one such approach. In this literature review, we will summarize the current knowledge from both clinical and nonclinical studies on the effects of adenosine A2A receptor blockade on dyskinesia.
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PMID:Clinical/pharmacological aspect of adenosine A2A receptor antagonist for dyskinesia. 2517 64

Altered dopaminergic neurotransmission in the basal ganglia is observed in Parkinson's disease (PD) and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID). An attractive alternative for treating LID is to use adjunct drugs to modulate nondopaminergic neurotransmitter systems in the basal ganglia. For example, adenosine receptors have received attention over the past years for the treatment of PD and LID. Adenosine interacts closely with dopamine and plays an important role in the function of striatal GABAergic efferent neurons. Excitatory glutamatergic neurotransmission is also modulated by adenosine in the striatum. Hence, based on the unique cellular and regional distribution of this system, adenosine neurotransmission could have an important implication for the development of new therapeutic strategies targeting the basal ganglia disorders. Indeed, A2A adenosine receptor antagonists were shown to improve motor deficits in PD and to reduce the severity of LID. A2A receptor subtypes are selectively found on striatopallidal neurons and can couple with receptors of interest in PD, such as D2 dopamine and metabotropic glutamate receptor type 5 (mGlu5) receptors, and form functional heteromeric complexes. This chapter will review relevant studies investigating the role and contribution of adenosine receptor subtypes in pathophysiology of PD and LID. The interactions of adenosine receptors, especially A1 and A2A receptor subtypes, with other receptors implicated in the pathophysiology of PD and LID such as dopaminergic and glutamatergic receptors will be reviewed. The implication of these interactions in the development and expression of PD symptoms and LID needs further investigation to find novel drug targets.
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PMID:Interaction of adenosine receptors with other receptors from therapeutic perspective in Parkinson's disease. 2517 65

Adenosine and adenosine receptors (ARs) are increasingly recognized as important therapeutic targets for controlling cognition under normal and disease conditions for its dual roles of neuromodulation as well as of homeostatic function in the brain. This chapter first presents the unique ability of adenosine, by acting on the inhibitory A1 and facilitating A2A receptor, to integrate dopamine, glutamate, and BNDF signaling and to modulate synaptic plasticity (e.g., long-term potentiation and long-term depression) in brain regions relevant to learning and memory, providing the molecular and cellular bases for adenosine receptor (AR) control of cognition. This led to the demonstration of AR modulation of social recognition memory, working memory, reference memory, reversal learning, goal-directed behavior/habit formation, Pavlovian fear conditioning, and effort-related behavior. Furthermore, human and animal studies support that AR activity can also, through cognitive enhancement and neuroprotection, reverse cognitive impairments in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and schizophrenia. Lastly, epidemiological evidence indicates that regular human consumption of caffeine, the most widely used psychoactive drug and nonselective AR antagonists, is associated with the reduced cognitive decline in aging and AD patients, and with the reduced risk in developing PD. Thus, there is a convergence of the molecular studies revealing AR as molecular targets for integrating neurotransmitter signaling and controlling synaptic plasticity, with animal studies demonstrating the strong procognitive impact upon AR antagonism in normal and disease brains and with epidemiological and clinical evidences in support of caffeine and AR drugs for therapeutic modulation of cognition. Since some of adenosine A2A receptor antagonists are already in phase III clinical trials for motor benefits in PD patients with remarkable safety profiles, additional animal and human studies to better understand the mechanism underlying the AR-mediated control of cognition under normal and disease conditions will provide the required rationale to stimulate the necessary clinical investigation to rapidly translate adenosine and AR drug as a novel strategy to control memory impairment in neuropsychiatric disorders.
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PMID:Adenosine receptor control of cognition in normal and disease. 2517 70

Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinson's disease (PD). We have characterized the dual adenosine A2A/A1 receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50's of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D2 antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinson's disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD.
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PMID:JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease. 2520 19

The current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson's disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson's disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson's disease.
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PMID:Caffeine as a lead compound for the design of therapeutic agents for the treatment of Parkinson's disease. 2554 41

Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.
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PMID:History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents. 2582 Nov 94

Adenosine A1 receptors are attracting great interest as drug targets for their role in cognitive deficits. Antagonism of the adenosine A1 receptor may offer therapeutic benefits in complex neurological diseases, such as Alzheimer's and Parkinson's disease. The aim of this study was to discover potential selective adenosine A1 receptor antagonists. Several analogs of 8-(3-phenylpropyl)xanthines (3), 8-(2-phenylethyl)xanthines (4) and 8-(phenoxymethyl)xanthines (5) were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that the 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d), among each series, displayed the highest affinity for the adenosine A1 receptor with Ki values in the nanomolar range. This ethyl-substitution pattern was previously unknown to enhance adenosine A1 receptor binding affinity. The 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d) behaved as adenosine A1 receptor antagonists in GTP shift assays performed with either rat cortical or whole brain membranes expressing adenosine A1 receptors. Further, in vivo evaluation of 3d showed reversal of adenosine A1 receptor agonist-induced hypolocomotion. In conclusion, the most potent evaluated compound, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (3d), showed both in vitro and in vivo activity, and therefore represent a novel adenosine A1 receptor antagonist that may have potential as a drug candidate for dementia disorders.
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PMID:1,3,7-Triethyl-substituted xanthines--possess nanomolar affinity for the adenosine A1 receptor. 2639 70


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