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Concept: CGS-21680


Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. Here, we show that the adenosine A2a receptor (ADORA2A) promotes hypoxia-inducible transcription factor-1 (HIF-1)-dependent endothelial cell glycolysis, which is crucial for pathological angiogenesis in proliferative retinopathies. Adora2a expression is markedly increased in the retina of mice with oxygen-induced retinopathy (OIR). Endothelial cell-specific, but not macrophage-specific Adora2a deletion decreases key glycolytic enzymes and reduces pathological neovascularization in the OIR mice. In human primary retinal microvascular endothelial cells, hypoxia induces the expression of ADORA2A by activating HIF-2α. ADORA2A knockdown decreases hypoxia-induced glycolytic enzyme expression, glycolytic flux, and endothelial cell proliferation, sprouting and tubule formation. Mechanistically, ADORA2A activation promotes the transcriptional induction of glycolytic enzymes via ERK- and Akt-dependent translational activation of HIF-1α protein. Taken together, these findings advance translation of ADORA2A as a therapeutic target in the treatment of proliferative retinopathies and other diseases dependent on pathological angiogenesis.Pathological angiogenesis in the retina is a major cause of blindness. Here the authors show that adenosine receptor A2A drives pathological angiogenesis in the oxygen-induced retinopathy mouse model by promoting glycolysis in endothelial cells via the ERK/Akt/HIF-1α pathway, thereby suggesting new therapeutic targets for disease treatment.

Concepts: Protein, Gene, Adenosine triphosphate, Adenosine receptor, Glycolysis, Adenosine A2A receptor, Adenosine A1 receptor, CGS-21680


Context: Foot ulcer is the principal cause of hospitalization for patients with diabetes. Polydeoxyribonucleotide (PDRN), an adenosine A2A receptor agonist, improves wound healing in diabetic mice. Objective: Aim of this study was to evaluate the effect of PDRN on chronic ulcer healing in patients with diabetes. Design and Setting: This randomized, double-blind, placebo-controlled trial, involved 2 medical centers in Italy. Intervention: Patients with diabetes showing hard-to-heal ulcers (Wagner grade 1 or 2), were randomly assigned to receive placebo (n=106) or PDRN (n=110). The treatments (PDRN and placebo) were performed three days a week for 8 weeks, by intramuscular and peri-lesional route. Main outcome measures: The primary outcome was complete ulcer healing. Secondary outcomes were the days needed to complete wound closure and the re-epithelialization of wound surface (as % of the original area). Results: After 8 weeks, 91 placebo and 101 PDRN subjects completed the study. Complete healing was achieved in 18.9% (95%CI 11.4-26.3) of placebo and in 37.3% (95%CI 28.2-46.3) of PDRN treated patient (p=0.0027). After 8 weeks, PDRN increases the closure of foot ulcers in diabetic subjects (HR= 2.20; 95% CI 1.29-3.75; p=0.004). The median time to complete wound healing, was 49 days for placebo (range 28-56) and 30 days for PDRN treated subjects (range 14-56; P=0.0027). The median epithelialized area of the ulcers (expressed as %), was 49.3% in the placebo and 82.2% in the PDRN group (P<0.001). Conclusions: PDRN facilitates healing of Wagner 1 or 2 diabetic foot ulcers.

Concepts: Adenosine receptor, Adenosine A2A receptor, Adenosine A1 receptor, Diabetic foot, CGS-21680


In recent years, many studies have demonstrated that endogenous adenosine induced by ischemia postconditioning reduces apoptosis in animal and cell models, but no study has clearly elucidated the effects of hypoxia postconditioning (HPC) in human dermal microvascular endothelial cells (HDMECs) of flaps, and the subtype of adenosine receptors involved remains unknown. In our study, we sought to identify the roles of adenosine A2a receptor, NDRG3 (N-myc downstream-regulated gene 3) and Raf-ERK pathway in the anti-apoptotic effects of hypoxia postconditioning.

Concepts: Protein, Organism, Chromosome, Hypoxia, Adenosine receptor, Adenosine A2A receptor, Adenosine A1 receptor, CGS-21680


Among non-dopaminergic strategies for combating Parkinson’s disease (PD), antagonism of A2A adenosine receptor (AR) has emerged to show great potential. In this study, based on the two crystal structures of A2A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A2A AR antagonists. A total of 63 structurally diverse compounds identified by VS were submitted to experimental testing, and 11 of them exhibited substantial activity against A2A AR (Ki < 10 μM), including two compounds with Ki below 1 μM (compound 43: 0.42 μM and compound 51: 0.27 μM) and good A2A/A1 selectivity (fold < 0.1). Compounds 43 and 51 demonstrated antagonistic activity according to the results of cAMP measurements (cAMP IC50 = 1.67 and 1.80 μM, respectively) and showed good efficacy in the haloperidol-induced catalepsy (HIC) rat model for PD at the dose up to 30 mg/kg. Further lead optimization based on substructural searching strategy led to the discovery of compound 84 as an excellent A2A AR antagonistic activity (A2A Ki = 54 nM, A2A/A1 fold < 0.1, cAMP IC50 = 0.3 μM) with significant improvement in anti-PD efficacy in the HIC rat model.

Concepts: Pharmacology, Signal transduction, Receptor antagonist, Agonist, Adenosine receptor, Adenosine A2A receptor, Adenosine A1 receptor, CGS-21680


Selected adenosine A2A receptor agonists (PSB-15826, PSB-12404, and PSB-16301) have been evaluated as new antiplatelet agents. In addition, radioligand-binding studies and receptor-docking experiments were performed in order to explain their differential biological effects on a molecular level. Among the tested adenosine derivatives, PSB-15826 was the most potent compound to inhibit platelet aggregation (EC50 0.32 ± 0.05 µmol/L) and platelet P-selectin cell-surface localization (EC50 0.062 ± 0.2 µmol/L), and to increase intraplatelets cAMP levels (EC50 0.24 ± 0.01 µmol/L). The compound was more active than CGS21680 (EC50 0.97±0.07 µmol/L) and equipotent to NECA (EC50 0.31 ± 0.05 µmol/L) in platelet aggregation induced by ADP. In contrast to the results from cAMP assays, Ki values determined in radioligand-binding studies were not predictive of the A2A agonists' antiplatelet activity. Docking studies revealed the key molecular determinants of this new family of adenosine A2A receptor agonists: differences in activities are related to π-stacking interactions between the ligands and the residue His264 in the extracellular loop of the adenosine A2A receptor which may result in increased residence times. In conclusion, these results provide an improved understanding of the requirements of antiplatelet adenosine A2A receptor agonists.

Concepts: Pharmacology, Antiplatelet drug, Receptor antagonist, Serotonin, Adenosine receptor, CGS-21680


Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by abnormal social interactions, repetitive behaviors that impair social communication, and circumscribed interests. BTBR T+tf/J (BTBR) inbred mice are generally used as a model for ASD, as they show repetitive behaviors and social deficits that resemble signs of ADS in humans. Adenosine A2A receptors (A2ARs) are considered as potential targets in the treatment of immune, inflammatory, and neurodegenerative diseases. In this study, we investigated the potential effects of the A2A adenosine receptor (A2AR) antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on behavior (self-grooming), hot plate test results, and expression levels of IL-17A(+), RORγt(+), Foxp3(+), and IL-10(+) in CD4(+) T spleen cells in BTBR and C57BL/6 (B6) mice. We also assessed IL-17A, RORγt, Stat3, pStat3, Foxp3, and IL-10 mRNA and protein expression levels in the brain tissue. The CGS-treated mice showed a significantly altered self-grooming score and a reduced response to the hot plate test. The results further revealed that the SCH efficiently increased the IL-17A(+) and RORγt(+) expression levels and decreased the Foxp3(+) and IL-10(+) expression levels in CD4(+) cells. However, the treatment with CGS significantly reversed these effects. In addition, CGS significantly decreased the IL-17A, RORγt, Stat3, and pStat3 levels and increased the Foxp3 and IL-10 mRNA and protein expression levels as compared with the BTBR control and SCH treatments. Our results clearly indicate that the CGS A2AR agonist may represent a unique target for future therapeutic strategies for neuroimmune dysfunction.

Concepts: Protein, Receptor, Autism, Autism spectrum, Adenosine receptor, Adenosine A2A receptor, Adenosine A1 receptor, CGS-21680


Retinopathy of prematurity (ROP) is the leading cause of childhood blindness, but current anti-VEGF therapy is concerned with delayed retinal vasculature, eye, and brain development of preterm infants. The clinical observation of reduced ROP severity in premature infants after caffeine treatment for apnea suggests that caffeine may protect against ROP. Here, we demonstrate that caffeine did not interfere with normal retinal vascularization development but selectively protected against oxygen-induced retinopathy (OIR) in mice. Moreover, caffeine attenuated not only hypoxia-induced pathologic angiogenesis, but also hyperoxia-induced vaso-obliteration, which suggests a novel protection window by caffeine. At the hyperoxic phase, caffeine reduced oxygen-induced neural apoptosis by adenosine A2A receptor (A2AR)-dependent mechanism as revealed by combined caffeine and A2AR knockout treatment. At the hypoxic phase, caffeine reduced microglial activation and enhanced tip cell formation by A2AR-dependent and -independent mechanisms as combined caffeine and A2AR knockout produced additive and nearly full protection against OIR. Together with clinical use of caffeine in neonates, our demonstration of the selective protection against OIR, effective therapeutic window, adenosine receptor mechanisms, and neuroglial involvement provide the direct evidence of the novel effects of caffeine therapy in the prevention and treatment of ROP.-Zhang, S., Zhou, R., Li, B., Li, H., Wang, Y., Gu, X., Tang, L., Wang, C., Zhong, D., Ge, Y., Huo, Y., Lin, J., Liu, X.-L., Chen, J.-F. Caffeine preferentially protects against oxygen-induced retinopathy.

Concepts: Signal transduction, Caffeine, Protection, Adenosine receptor, Adenosine A2A receptor, Preterm birth, Adenosine A1 receptor, CGS-21680


Adenosine receptor A2A antagonists have emerged as potential treatment for Parkinson’s disease in the past decade. We have recently reported a series of adenosine receptor antagonists using heterocycles as bioisosteres for a potentially unstable acetamide. These compounds, while showing excellent potency and ligand efficiency, suffered from moderate cytochrome P450 inhibition and high clearance. Here we report a new series of adenosine receptor A2A antagonists based on a 4-amino-5-carbonitrile pyrimidine template. Compounds from this new template exhibit excellent potency and ligand efficiency with low cytochrome P450 inhibition. Although the clearance remains moderate to high, the leading compound, when dosed orally as low as 3 mg/kg, demonstrated excellent efficacy in the haloperidol induced catalepsy rat model for Parkinson’s disease.

Concepts: Receptor, Parkinson's disease, Cytochrome P450, Receptor antagonist, Adenosine receptor, Adenosine A2A receptor, Adenosine A1 receptor, CGS-21680


The association and dissociation kinetics of ligands binding to proteins vary considerably, but the mechanisms behind this variability are poorly understood, limiting their utilization for drug discovery. This is particularly so for GPCRs where high resolution structural information is only beginning to emerge. Engineering the human A2A adenosine receptor has allowed structures to be solved in complex with the reference compound ZM241385 and four related ligands at high resolution. Differences between the structures are limited, with the most pronounced being the interaction of each ligand with a salt bridge on the extracellular side of the receptor. Mutagenesis experiments confirm the role of this salt bridge in controlling the dissociation kinetics of the ligands from the receptor, while molecular dynamics simulations demonstrate the ability of ligands to modulate salt bridge stability. These results shed light on a structural determinant of ligand dissociation kinetics and identify a means by which this property may be optimized.

Concepts: Protein, Pharmacology, Chemistry, Adenosine receptor, Adenosine A2A receptor, Adenosine A1 receptor, CGS-21680, ZM-241,385


Multiple sclerosis (MS) is a common autoimmune disease that inevitably causes inflammatory nerve demyelination. However, an effective approach to prevent its course is still lacking and urgently needed. Recently, the adenosine A2A receptor (A2AR) has emerged as a novel inflammation regulator. Manipulation of A2AR activity may suppress the MS process and protect against nerve damage. To test this hypothesis, we treated murine experimental autoimmune encephalomyelitis (EAE), a model for MS, with the selective A2AR agonist, CGS21680 (CGS). We evaluated the effects of CGS on the pathological features of EAE progression, including CNS cellular infiltration, inflammatory cytokine expression, lymphocyte proliferation, and cell surface markers. Treatment with CGS significantly suppressed specific lymphocyte proliferation, reduced infiltration of CD4(+) T lymphocytes, and attenuated the expression of inflammatory cytokines, which in turn inhibited the EAE progression. For the first time, we demonstrate that CGS can increase the intracellular calcium concentration ([Ca(2+)]i) in murine lymphocytes, which may be the mechanism underlying the suppressive effects of CGS-induced A2AR activation on EAE progression. Our findings strongly suggest that A2AR is a potential therapeutic target for MS and provide insight into the mechanism of action of A2AR agonists, which may offer a therapeutic option for this disease.

Concepts: Immune system, Antibody, Cytokine, Natural killer cell, B cell, Multiple sclerosis, Adenosine receptor, CGS-21680