CGS 21680 / Novartis - LARVOL DELTA

Interaction between purinergic signalling and purinergic modulators with skin wound repair effectors: a systematic review of preclinical in vivo models. (PubMed, Purinergic Signal) - "Topical or oral administration of CGS-21680 (4-[{N-ethyl-5'-carbamoyladenos-2-yl}aminoethyl] phenylpropionic acid), UTP (Uridine-5'-triphosphate), NECA (5'-N-ethylcarboxamidoadenosine), ATP (adenosine triphosphate), PDRN (polydeoxyribonucleotide), ADP (Adenosine-5'-diphosphate) and TMPS (Thymidine 5'-O-monophosphorothioate) agonists stimulated wound contraction, fibroblast and keratinocyte proliferation, angiogenesis, and collagen biosynthesis...Conversely, the purinergic antagonists DMPX (3,7-dimethyl-1-propargylxanthine), CSC (8-(3-chlorostyryl) caffeine), SUR (Suramin), ENP (enprofylline), caffeine, CLOP (clopidogrel), MRS 2179 (2'-deoxy-N6-methyladenosine-3',5'-bisphosphate), and MRS 2395 (2-Chloro-3',5'-O-(benzoyl-β,γ-methylene) adenosine 5'-triphosphate), as well as genetic knockout for purinergic receptors delayed wound closure by inhibiting these pathways, impairing angiogenesis, collagenogenesis, and aggravating..."

Journal • Preclinical • Review • Inflammation • EGF • IL10 • IL13 • TGFB1

Pulsed Electromagnetic Field Exposure Attenuates Ultraviolet B-Induced Dermal Collagen Loss in Association with A2A Adenosine Receptor Signaling. (PubMed, Int J Mol Sci) - "In UVB-exposed fibroblasts, PEMF restored A2AAR and PKA protein levels, cAMP levels, and the pNLRP3/NLRP3 ratio, similar to the effects of the A2AAR agonist CGS-21680...These findings are consistent with, but do not prove, involvement of A2AAR/cAMP/PKA-related signaling and inhibitory NLRP3 phosphorylation in the PEMF response. These results should be interpreted as evidence from a UVB-specific experimental model rather than a comprehensive model of solar photoaging."

Journal • Inflammation • IL1B • MMP2 • MMP3 • MMP9 • NLRP3

ADORA2A activation restores lysosomal function and photoreceptor outer segment degradation in stressed retinal pigment epithelium. (PubMed, Front Physiol) - "In sodium iodate-injured mice, CGS21680 preserved outer retinal structure, reduced FITC-BSA leakage, improved electroretinographic responses, and was accompanied by increased CREB phosphorylation and recovery of Cathepsin D proteolytic competence. ADORA2A activation promotes Rubicon-associated, lysosome-dependent LC3 processing of internalized POS and restores lysosomal degradative competence, supporting ADORA2A as a potential therapeutic target for early AMD."

Journal • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • ADORA2A • CTSD

Bifidobacterium Pseudolongum-Derived Inosine Mitigates Polystyrene Nanoplastics-Induced Hepatic Injury by Inhibiting the Polarization of M1 Macrophages. (PubMed, Adv Sci (Weinh)) - "CGS21680, an agonist of A2AR, effectively represses lipopolysaccharide (LPS)-induced M1 macrophage polarization and inhibits the miR155/SOCS1/NF-κB pathway in vitro...These findings suggest that B.p-derived inosine can repress NPs-induced M1 macrophages polarization by inhibiting the miR155/SOCS1/NF-κB pathway via targeting A2AR. Altogether, this study further clarifies the role of gut microbiota in NPs-induced hepatic injury and provides a potential microbial therapeutic strategy."

Journal • Hepatology • Liver Failure • MIR155 • SOCS1

Bifidobacterium pseudolongum-derived inosine mitigates polystyrene nanoplastics-induced hepatic injury by inhibiting the polarization of M1 macrophages (EASL 2026) - "In vitro, CGS21680 (an agonist of A2AR) repressed lipopolysaccharide (LPS)-induced polarization of M1 macrophages by inhibiting the miR155/SOCS1/NF-κB pathway... Gut microbiota partly mediates NPs-induced hepatic injury. B.p-derived inosine represses NPs-induced M1 macrophages polarization by inhibiting the miR155/SOCS1/NF-κB pathway via targeting A2AR. Our findings further clarifies the role of gut microbiota in NPs-induced hepatic injury and provides a potential microbial therapeutic strategy."

Hepatology • Liver Failure • MIR155 • SOCS1

A2A Receptor Activation Restores Lipid and Mitochondrial Homeostasis, Limiting Mycobacterium leprae Persistence in Human Monocytes. (PubMed, Metabolites) - "CGS21680 also restored Δψm and decreased intracellular M. leprae viability. Our data suggest that M. leprae suppresses A2AR signaling to favor its survival in monocytes, indicating that the extracellular ADO-A2AR pathway may be a potential target to limit early M. leprae infection."

Journal • Infectious Disease • ADORA2A • ENTPD1 • SLC29A1

Caffeine inhibited the hyperoxia-induced A2AR-ERK/p38 MAPK-IL-8 pathway in type II alveolar epithelial cells to suppress NETs formation in bronchopulmonary dysplasia. (PubMed, Pediatr Res) - "Caffeine inhibited hyperoxia-induced NETs formation and exerts a protective effect on bronchopulmonary dysplasia (BPD). Caffeine reduces hyperoxia-induced A549 cell injury and NETs secretion by inhibiting the A2AR-ERK/p38 MAPK-IL-8 pathway. This research offers a new theoretical foundation for comprehending how caffeine improves neonatal BPD. These findings provide a theoretical basis for developing therapeutic strategies targeting NETs. This research offers new insights for improving the prognosis of premature infants with BPD."

Journal • Bronchopulmonary Dysplasia • Pulmonary Disease • Respiratory Diseases • CXCL8 • CXCR2

Adenosine A2a receptors offset cholinergic control of blood pressure, autonomic neuropathy, and brainstem neuroinflammation in sepsis. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Intracisternal (i.c.) administration of CGS21680 (A2aAR agonist, 2 μg/rat) accentuated the hypotensive response to sepsis on its own and blunted the rises in blood pressure caused by subsequently administered nicotine...On the other hand, the interrelated cardiovascular and molecular effects of nicotine were maintained following central blockade of A2aARs by 8-(3-chlorosteryl) caffeine (CSC, 40 μg/rat i.c.). The data suggest that medullary A2aARs restrain the machinery by which the cholinergic antiinflammatory pathway acts defensively to rectify cardiovascular and autonomic consequences of sepsis."

Journal • Cardiovascular • CNS Disorders • Depression • Hypotension • Infectious Disease • Inflammation • Oncology • Pain • Psychiatry • Septic Shock • ADORA2A • TNFA

Receptor-Specific Adenosine Signalling Governs Astrocyte Glycogen Homeostasis. (PubMed, Aging Dis) - "We probed receptor contributions using adenosine and selective agonists (CCPA, A1; CGS21680, A2A; BAY 60-6583, A2B)...Selective A2B activation produced a significant increase in intracellular lactate compared with vehicle. Together, these data identify A2B signalling as a principal driver of acute glucose mobilisation while slowing glycogen replenishment in astrocytes, operating through cAMP elevation and sustained Ca2+ signals, whereas A2A preferentially promotes perinuclear glycogen accumulation."

Journal

Involvement of Adenosine A2A Receptors in Anxiety-Like Behaviors in Tetrahydrocannabinol-Treated Mice. (PubMed, Brain Behav) - "These findings contribute to the understanding of THC's complex pharmacological actions, highlighting the importance of receptor cross talk in modulating anxiety and other behavioral outcomes."

Journal • Preclinical • Mood Disorders • Psychiatry • ADORA2A

Inhibition of A2AR alleviates adenosine-mediated suppression of plasma cell differentiation. (PubMed, Front Immunol) - "In vitro differentiated B cells and sorted tonsillar B cells were stimulated in the presence of the A2AR agonist CGS-21680 with or without the A2AR antagonist inupadenant, and analysed by flow cytometry, LegendPLEX and scRNA-seq. Spatial transcriptomics analysis of tumor biopsies from patients treated with inupadenant revealed that ASCs specifically increased in tertiary lymphoid structures. Altogether, these data demonstrate that A2AR plays a key role in adenosine-mediated inhibition of B cell maturation toward ASCs through a B cell-intrinsic mechanism, and that this effect is fully reverted by inupadenant."

Journal • Multiple Myeloma • Oncology

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