CGS 21680 / Novartis - LARVOL DELTA

Adenosine pathway as a therapeutic target in diffuse large B cell lymphoma (ASH 2025) - "Shortstimulation with A2AR agonist (CGS-21680) causes an increase in intracellular cAMP in some cell lines(HBL-1, Ly7, Ly1) but not in others (Ly19, Ly10). This increase in cAMP can be reverted with A2ARantagonists (ciforadenant and istradefylline)...Ciforadenant at both doses increased survival in B6but not in NOD-SCID mice, with time of death considered when tumors reached 2 cm and mice wereeuthanized (Log rank (Mantel-Cox) test p=0.019). Taken together our results demonstrate that DLBCLcells are resistant to the inhibitory effects of eADO seen in normal B cells, and that A2AR antagonists areeffective for the treatment DLBCL via an immune mediated mechanism in a preclinical model of DLBCL."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Solid Tumor • BCL2 • CD38 • CD73 • ENTPD1 • HLA-C • LY9 • NT5E • SDC1

Postconditioning with NECA attenuates cardiac I/R injury by engaging A2AR-PKCα signaling in diabetic rat. (PubMed, Int Immunopharmacol) - "Pharmacological blockade of the A2A receptor with ZM241385 abolished NECA's benefits, while the A2AR agonist CGS21680 and PKCα activator PMA reproduced them. Electrophoretic mobility shift assays confirmed a direct interaction between PKCα and pri-miR-15a, suggesting transcriptional regulation. Collectively, these findings demonstrate that NECA attenuates myocardial I/R injury in diabetic rats through activation of the A2AR-PKCα signaling axis and inhibition of miR-15a, offering a potential therapeutic strategy for diabetic patients at risk of ischemic cardiac events."

IO biomarker • Journal • Preclinical • Cardiovascular • Diabetes • Metabolic Disorders • Myocardial Infarction • Reperfusion Injury • Type 2 Diabetes Mellitus • ADORA2A • BCL2 • CASP3 • MIR15A • TNNI3

Exploration of Purinergic Signaling Pathways As a Mechanism of Platelet Activation in Antiphospholipid Syndrome (ASH 2024) - "Adenosine, NECA (stable adenosine analogue), CGS21680 (A2A receptor agonist) were used to evaluate adenosine pathway signaling...Conclusion : Platelets from patients with t-PAPS display resistance to platelet inhibition via the adenosine pathway. The stimulation of adenosine pathway may form a potential therapeutic option to control hypercoagulability in APS."

Genetic Disorders • Hematological Disorders • ADORA2A • ITGA2B • ITGB3 • SELP • VTN

The Ectopyrase CD73 Is a Critical Checkpoint in Thromboinflammation (ASH 2024) - "Mechanistically, the severe thromboinflammation phenotype induced by genetic or post-natal CD73 inhibition in mice could be rescued by stimulation of the GPCR adenosine 2A receptor with CGS21680, suggesting CD73's enzymatic activity to generate adenosine and trigger downstream cAMP signaling as a key mechanism in mitigating venous thrombosis...Our ongoing studies will test whether a clinically used CD73 inhibitor is capable of triggering a thromboinflammatory phenotype in mice. These studies are especially relevant in the context of the large number of patients with prothrombotic cancers who may potentially receive a CD73 inhibitor for cancer treatment."

IO biomarker • Cardiovascular • Inflammation • Thrombosis • CD14 • CD73 • MPO

Adenosine A2A receptor modulation affects the development of depressive-like behaviour and dopamine D2 receptor availability in rats exposed to repeated social defeat. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Our study showed that the treatment with either an A2AR agonist or an A2AR antagonist prevented the development of depressive-like behaviour, and reduced the availability of D2 receptor in the striatum after exposure to RSD most likely by modulating the receptor affinity."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • ADORA2A • DRD2

Adenosine A2A receptor activation in the nucleus accumbens decreases motivation for wheel running in male mice. (PubMed, Psychopharmacology (Berl)) - "These findings demonstrate that, in male mice, A2A receptor activation selectively suppressed the appetitive component of wheel-running motivation, whereas A2A receptor blockade did not. Together, our results highlight the crucial role of NAc A2A receptors in regulating motivation for wheel running and suggest the potential therapeutic application of A2A receptor agonists for treating maladaptive behavioral over-engagement."

Journal • Preclinical • CNS Disorders • Psychiatry • ADORA2A

Cannabidiol releases CB1R from A2AR repression in ischemic stroke. (PubMed, Neurobiol Dis) - "Results indicated that the formation of A2AR-CB1R heteromers increased A2AR affinity for its selective agonist CGS21680...In conclusion, CBD effects in the hypoxia of the neonate can be mediated by A2AR-CB1R complex. CBD partially blocks A2AR signalling while potentiates the neuroprotective effect of CB1R in hypoxic-ischemic conditions."

Journal • Cardiovascular • Ischemic stroke

Adenosine A2AR agonist blocks mesenteric lymphatic epithelium, adipose tissue and Treg cells links of metabolic dysfunction-associated steatotic liver disease mice. (PubMed, Mol Cell Endocrinol) - "This treatment also led to reduced cytokine release and promoted a shift towards an M2 phenotype in RAW 264.7 macrophages. Overall, the A2AR agonist CGS21680 shows promise as a therapeutic agent to inhibit both adipose tissue inflammation and hepatic inflammation/fibrosis by disrupting pathogenic links between adipose tissue, mesenteric lymphatics, and splenic Treg cells in MASLD mice."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • ADORA2A • IL6 • LYVE1 • TNFA

Longitudinal imaging evaluation of the inflammatory role of purinergic A2A receptors during subacute and chronic ischemic stroke. (PubMed, J Cereb Blood Flow Metab) - "Furthermore, activation of A2ARs with the agonist CGS-21680 resulted in a reduction in stroke volume, along with an increase in TSPO expression in immune cells in the striatum. Our results provide novel evidence on A2ARs density dynamics after cerebral ischemia that might guide the therapeutic management of stroke by modulating adenosine receptors."

Journal • Cardiovascular • Inflammation • Ischemic stroke • ADORA2A

Urethane as an unparalleled anesthetic model for sleep cycling (WSS 2025) - "Stable rhythmic alternations with consistent proportions of activated (REM-like) and deactivated (non-REM-like) activity were recorded before i.v. or intra-cerebro-ventricular administrations of adenosine, caffeine, N6-cyclopentyladenosine (CPA), or CGS 21680... Adenosine and both its agonists and antagonists have parallel effects across urethane anesthesia and natural sleep. This is further evidence supporting the validity of the urethane model of sleep itself."

Anesthesia

Adenosine A2a Receptor Stimulation Mitigates Periodontitis and Is Mitoprotective in Gingival Fibroblasts Promoting Cellular Resilience. (PubMed, Cells) - "Here, we investigated the effects of selective adenosine A2a receptor (A2aR) stimulation using the agonist CGS21680 in a mouse model of ligature-induced periodontitis (LIP) and in gingival fibroblast mitochondrial function...Ultrastructural studies showed elongated, healthier mitochondria and increased pro-fusion markers, indicating enhanced mitochondrial quality control. Overall, A2aR stimulation attenuates periodontal inflammation and confers mitoprotective effects on gingival fibroblasts, supporting its potential as a therapeutic strategy to both mitigate periodontitis progression and preserve tissue bioenergetics supporting cellular resilience."

Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis • ADORA2A • CD73 • CXCL10 • CXCL12 • IL1B • TNFA

Cannabidiol biases A2A-CB2 receptor heteromer function by decoupling β-arrestin signaling from complex formation. (PubMed, Biochem Pharmacol) - "Notably, this effect was accompanied by functional dissociation: CBD inhibited β-arrestin II recruitment in a probe-dependent manner, with significant modulatory effects at concentrations of 100 nM, and showed a greater inhibition of the CB2R agonist JWH-133-induced signaling than that induced by CGS 21680, an A2AR agonist...Rather than disrupting heteromer formation, CBD selectively induces a conformational state that uncouples physical receptor interaction from β-arrestin II signaling. This defines a distinct mechanism of action for CBD and highlights A2AR-CB2R heteromers as promising targets for biased signaling-based therapeutics."

Journal

Antibody-drug conjugates to target G protein-coupled receptors (ACS-Fall 2025) - "In this work, we demonstrate for the first time that the linkage of a small molecule agonist (CGS21680, CGS) for the A2A adenosine receptor (A2AR) to a nanobody that binds to an engineered version of this receptor provides semi-synthetic nanobody-ligand conjugates with interesting and useful properties...Such nanobody-CGS conjugates exhibit activity that is contingent upon expression of both A2AR and the target of nanobody binding. This approach offers a path for the preferential activation of GPCRs only in cells or tissues that co-express the protein targeted by the nanobody found within nanobody-ligand conjugates."

The Role of Adenosine A1 and A2a Receptors in Cerebral Blood Vessel Reactivity of Sprague Dawley Rats Exposed to Hyperbaric Oxygenation. (PubMed, Molecules) - "This study investigated flow-induced dilation (FID) and hypoxia-induced dilation (HID) in the presence or absence of A1R/A2aR agonists (CCPA and CGS-21680, respectively) and antagonists (DPCPX and SCH-58261, respectively) in isolated middle cerebral arteries (MCAs) from Sprague Dawley rats of both sexes and the direct dose-dependent effects of A1R and A2aR agonists on the vascular reactivity of MCAs...Protein expression of A1R and A2aR decreased after Ac-HBO2, while gene expression increased following In-HBO2. These findings suggest that ARs play a role in HBO2-induced vasoreactivity, which possibly changes in MCA, potentially via the modulation of ARs gene and protein expression."

Journal • Preclinical • ADORA2A

Upregulation of VEGFA through the adenosine A2A receptor is a crucial pathway for inhibiting pericyte apoptosis in chronic cerebral hypoperfusion. (PubMed, Sci Rep) - "In this study, we induced CCH in Sprague‒Dawley rats via bilateral carotid artery occlusion and treated them with the A2AR agonist CGS21680 or the A2AR antagonist SCH58261...Rap-1 suppression obviously reduced the levels of phosphorylated ERK, VEGFA and VEGFR2 in pericytes, suggesting a role for the Rap1-ERK pathway in the A2AR-induced upregulation of VEGFA expression. Overall, A2AR activation inhibits pericyte apoptosis and may exert neuroprotective effects against CCH by increasing VEGFA expression through the Rap1-ERK signaling pathway."

IO biomarker • Journal • Alzheimer's Disease • Cognitive Disorders • ADORA2A • BAX • BCL2 • CASP3 • KDR

Exploration of purinergic signaling pathways as a mechanism of platelet activation in antiphospholip (ISTH 2025) - "Methods Platelet-rich plasma was preincubated with adenosine and CGS21680 and tested for ADP- and collagen-induced aggregation...Median circulating ADA levels were 13.20 U/L (IQR 10.95-17.05) in patients and 9.70 U/L (IQR 8.00-11.10, p < 0.0001) in controls. Table or Figure Upload"

Genetic Disorders • Hematological Disorders • SLC29A1

The Platelet Adenosinergic Axis as a Potential Therapeutic Target for Antiphospholipid Syndrome (ISTH 2025) - "Boosting cAMP with A2AR agonists (CGS21680) or PDE3 inhibitors (cilostazol) was especially effective in limiting platelet activation. Table or Figure Upload"

Cardiovascular • Genetic Disorders • Hematological Disorders • CD73 • SELP

In Situ Mass Spectrometry Imaging to Elucidate the Effects of an Adenosine A2A Receptor Agonist and Alprazolam on Sleep Regulation. (PubMed, ACS Pharmacol Transl Sci) - "CGS21680 (CGS), a selective agonist of the adenosine A2A receptor, exhibits neuroinhibitory properties. The coadministration of Alp and CGS resulted in the regulation of GABA, glutamate, and glutamine during the sleep latency and sleep maintenance periods, respectively. In conclusion, the potentiating effect of CGS on the sleep-inducing properties of Alp is attributed to its ability to modulate the distribution of Alp in the brain by enhancing BBB permeability and its influence on Alp-induced neurotransmitter release."

Journal • CNS Disorders • ADORA2A

Mitochondrial Localization and Function of Adenosine Receptors. (PubMed, Int J Biol Sci) - "Moreover, exposure of isolated mitochondria to selective A1, A2A and A2B receptors agonists revealed these receptors as potential modulators of mitochondrial energy metabolism, since ATP production and coupling efficiency increased in the presence of BAY 60-6583 (A2B agonist) whereas proton leak and acute response were higher with CGS 21680 (A2A agonist). Also, proton leak, ATP production, acute response and acute respiration were increased in the presence of CPA (A1 agonist). Interestingly, different mitochondrial morphological changes were detected in HeLa cells exposed to these receptors' agonists."

Journal

Macrophage A2aR Alleviates LPS-Induced Vascular Endothelial Injury and Inflammation via Inhibiting M1 Polarisation and Oxidative Stress. (PubMed, J Cell Mol Med) - "Conversely, the pretreatment with CGS21680 in vivo and in vitro showed corresponding improvement in functions of vascular endothelial dysfunction. These data demonstrate that A2aR in macrophages represents a promising novel therapeutic target for LPS-induced uncontrolled vascular endothelial injury and inflammation potentially through reducing macrophage M1 polarisation and OS and inhibiting the production and release of TNF-α production."

Journal • Infectious Disease • Inflammation • Oncology • Septic Shock • ADORA2A • ICAM1 • TERC • TNFA

Brain lipidomic profiles of sleep enhancement through co-administration of alprazolam and CGS21680. (PubMed, FEBS Lett) - "Other lipid classes exhibited reductions, with fatty acids decreasing in 10 regions, carnitines in seven regions, ceramides in nine regions, and diacylglycerols in 10 regions. The research provides valuable insights into sleep-related regulation pathways by delineating the regulation of various lipid biomarkers in multiple brain regions."

Journal • Anesthesia

Investigation of the Roles of the Adenosine A(2A) and Metabotropic Glutamate Receptor Type 5 (mGlu5) Receptors in Prepulse Inhibition and CREB Signaling in a Heritable Rodent Model of Psychosis. (PubMed, Cells) - "Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis."

Journal • Preclinical • CNS Disorders • Psychiatry • DRD2

Therapeutic effects of CGS21680, a selective A2A receptor agonist, via BDNF-related pathways in R106W mutation Rett syndrome model. (PubMed, Biomed Pharmacother) - "This is the first study to report the therapeutic effect of CGS21680 in R106W point mutation RTT models, both in vitro and in vivo. These research results suggest that CGS21680 could be a promising therapeutic candidate for the treatment of RTT."

Journal • CNS Disorders • Developmental Disorders • Movement Disorders • ADORA2A • BDNF

Comparing adenosine A2A receptor modulation of cannabinoid CB1 receptor-mediated inhibition of GABA and glutamate release in rodent striatal nerve terminals. (PubMed, Eur J Neurosci) - "The A2AR-selective agonist CGS21680 (30 nM) and the A2AR-selective antagonist SCH58261 (100 nM) dampened the inhibitory action of WIN55212-2 in rat synaptosomes...CB1R Bmax and KD were reduced in A2AR KO mice, whereas A2AR Bmax was smaller in CB1R KO mice. Altogether, our data reveal an intricate interdependence of presynaptic A2ARs and CB1Rs on striatal neuromodulation."

Journal • Preclinical • ADORA2A

The A2AR antagonist inupadenant promotes humoral responses in preclinical models (ESMO-IO 2024) - "The A2AR agonist CGS-21680 (in vitro and scRNAseq) or ATP (ex vivo) were added to trigger A2AR signaling, and B cells were stimulated with CpG (scRNAseq) or CD40L (ex vivo). This process is essential to produce high affinity antibodies and potentially for sustained anti-tumor immunity. Additional work is ongoing to confirm this novel mechanism in inupadenant-treated patients."

Preclinical • Lung Cancer • Oncology • Solid Tumor • ADORA2A • AICDA • CD40LG