Search

BackgroundLong-term use of levodopa (l-dopa) is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson’s disease.MethodsIn this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID).ResultsNine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM) score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD) estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD −0.00, 95% confidence interval (CI): −2.52 to 2.52, p = 1.0), superiority in improvement of motor disability (SMD −5.06, 95% CI: −9.25 to −0.87, p = 0.02) and more effective in control of AIM (SMD −1.82, 95% CI: −3.38 to −0.25, p = 0.02).ConclusionTo sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.

Parkinson’s disease affects millions of people around the world. Recently, adenosine A2Areceptor antagonists have been identified as a drug target for the treatment of Parkinson’s disease. Consequently, there is an immediate need to develop new classes of A2Areceptor antagonists. In the present analysis, three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were performed on a series of pyrimidines, using comparative molecular field analysis (CoMFA). The best prediction was obtained with a CoMFA standard model (q2= 0.475,r2= 0.977) and a CoMFA region focusing model (q2= 0.637,r2= 0.976) combined with steric and electrostatic fields. The structural insights derived from the contour maps helped to better interpret the structure–activity relationships. Also, to understand the structure–activity correlation of A2Areceptor antagonists, we have carried out molecular docking analysis. Based on the results obtained from the present 3D-QSAR and docking studies, we have identified some key features for increasing the activity of compounds, which have been used to design new A2Areceptor antagonists. The newly designed molecules showed high activity with the obtained models. [ABSTRACT FROM PUBLISHER]

Parkinson's disease (PD) is a chronic, progressive disease of the central nervous system (CNS), characterized by a slow loss of dopaminergic neurons in the substantia nigra, leading to significant decrease in dopamine (DA) levels in the striatum. Currently used drugs, such as levodopa (L-DOPA), amantadine, dopamine agonists (D) or anticholinergic drugs, are not effective enough, and do not eliminate the causes of disease. Many research centers are conducting research on new forms of currently used drugs (e.g. Duodopa, XP21279, IPX066), new drugs of already known groups (e.g. safinamide), medicines that suppress side effects of L-DOPA (e.g. AFQ056, fipamezole), and, finally, compounds with a novel mechanism of action (e.g. PMY50028, A2A receptor antagonists). A lot of scientific reports indicate an important role of A2A receptors in the regulation of the central movement system, so a new group of compounds - selective antagonists of A2A receptors (e.g. istradefylline, preladenant, SYN115) - has been developed and their potential use in PD has been examined. Clinical studies of A2A receptor antagonists have shown that this group of compounds can shorten off periods and at the same time they do not worsen dyskinesias in patients with PD. Moreover, there is ongoing research on new forms of treatment, such as gene therapy. Attempts to apply the viral vector AAV-2, which will be able to infect neurons with a variety of genes, including the gene of glutamate decarboxylase (GAD), neurturin (NTN), or aromatic L-amino acid decarboxylase, are currently being carried out. The results of phase I and II clinical studies showed some efficacy of this form of treatment, but the method requires further studies. An analysis of potential future therapies of Parkinson's disease suggests that some progress in this field has been made [ABSTRACT FROM AUTHOR]

Abstract: Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1–20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a K i value of 0.699μM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15–20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (K i =0.089 μM and 5-fold A1 selectivity). Structure–activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose. [Copyright &y& Elsevier]

Abstract: The adenosine A2A receptor has recently emerged as a leading non-dopaminergic therapeutic target for Parkinson''s disease, largely due to the restricted distribution of the receptor in the striatum and the profound interaction between adenosine and dopamine receptors in brain. Two lines of research in particular have demonstrated the promise of the A2A receptor antagonists as novel anti-parkinsonian drugs. First, building on extensive preclinical animal studies, the A2A receptor antagonist KW6002 has demonstrated its potential to increase motor activity in PD patients of the advanced stage in a recent clinical phase IIB trial. Second, recently two prospective epidemiological studies of large cohorts have firmly established the inverse relationship between the consumption of caffeine (a non-specific adenosine antagonist) and the risk of developing PD. The potential neuroprotective effect of caffeine and A2A receptor antagonists in PD is further substantiated by the demonstration that pharmacological blockade (by caffeine or specific A2A antagonists) or genetic depletion of the A2A receptor attenuated dopaminergic neurotoxicity and neurodegeneration in animal models of PD. Moreover, A2A receptor antagonism-mediated neuroprotection goes beyond PD models and can be extended to a variety of other brain injuries induced by stroke, excitotoxicity and mitochondrial toxins. Intensive investigations are under way to dissect out common cellular mechanisms (such as A2A receptor modulation of neuroinflammation) which may underlie the broad spectrum of neuroprotection by A2A receptor inactivation in brain. [Copyright &y& Elsevier]

The synthesis and in vitro structure–activity relationships (SAR) of a series of triazoles as A2A receptor antagonists is reported. This resulted in the identification of potent, selective and permeable 1,2,4-triazoles such as 42 for further optimization and evaluation in vivo. [Copyright &y& Elsevier]

In situ vaccination can trigger an antitumor immune response. However, the therapeutic effect is still limited since the high expression of adenosine binding to G protein-coupled receptor A2AR induces an immunosuppressive effect. In this work, a new formulation is presented with the combination of a nanovaccine based on redox-responsive polymer micelles and A2AR antagonist SCH58261. The micelles simultaneously encapsulate immunogenic cell death (ICD) inducer doxorubicin (DOX) and adjuvant toll-like receptor 7 and 8 (TLR7/8) agonist R848, acting as the potent in situ vaccines. A high concentration of glutathione in tumor cells leads to the disintegration of these micelles, releasing DOX and R848 to mediate ICD, inducing the activation of dendritic cells and initiating an immune response. Meanwhile, A2AR antagonist SCH58261, a generation immune checkpoint blocker, inhibits the immunosuppressive adenosinergic pathway in the tumor microenvironment, activating natural killer (NK) cells and CD8 + T cells, and inhibiting the proliferation of regulatory T cells. Therefore, this formulation can trigger a robust systemic antitumor immune response., (© 2021 Wiley-VCH GmbH.)

Background: Long-term use of levodopa (l-dopa) is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson's disease., Methods: In this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID)., Results: Nine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM) score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD) estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD -0.00, 95% confidence interval (CI): -2.52 to 2.52, p  = 1.0), superiority in improvement of motor disability (SMD -5.06, 95% CI: -9.25 to -0.87, p  = 0.02) and more effective in control of AIM (SMD -1.82, 95% CI: -3.38 to -0.25, p  = 0.02)., Conclusion: To sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.

Abstract: Parkinson''s disease (PD) is a severe neurodegenerative disorder, with no available drugs able to prevent the neuronal cell loss characteristic in brains of patients suffering from PD. Due to the complex cascade of molecular events involved in the etiology of PD, an innovative approach towards neuroprotection or neurorescue may entail the use of multifunctional pharmaceuticals that target an array of pathological pathways, each of which is believed to contribute to events that ultimately lead to neuronal cell death. Here we discuss examples of novel multifunctional ligands that may have potential as neuroprotective and neurorestorative therapeutics in PD. The compounds discussed originate from synthetic chemistry as well as from natural sources where various moieties, identified in research to possess neuroprotective and neurorestorative properties, have been introduced into the structures of several monomodal drugs, some of which are used in the clinic. [Copyright &y& Elsevier]

Introduction: Adenosine A2A receptors are localized in the brain, mainly within the caudate and putamen nuclei of the basal ganglia. Their activation leads to stimulation of the 'indirect' pathway. Conversely, administration of A2A receptor antagonists leads to inhibition of this pathway, which was translated into reduced hypomotility in several animal models of parkinsonism., Areas Covered: In this review, the effects of two A2A receptor antagonists, istradefylline and tozadenant, on parkinsonian symptoms in animal and humans will be discussed., Expert Opinion: Animal studies have shown potent antiparkinsonian effects for several A2A receptor antagonists, including istradefylline. In clinical trials, istradefylline reduced OFF time when administered with levodopa, but results are inconclusive. Results with tozadenant are scarce. Modification of thalamic blood flow compatible with reduced inhibition was noted in one small trial, followed by a significant reduction in OFF time in a larger one. Therefore, both drugs show promising efficacy for the reduction of OFF time in levodopa-treated Parkinson's disease patients, but further research is needed in order to obtain definitive conclusions.