CGS 21680 / Novartis - LARVOL DELTA

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

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 • Hematological Disorders • Inflammation • Oncology • Thrombosis • CD14 • CD73 • MPO

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

The Platelet Adenosinergic Axis as a Novel Therapeutic Target for Thrombotic APS (ACR Convergence 2024) - "Boosting cAMP with A2AR agonists (CGS21680) or PDE3 inhibitors (cilostazol) was especially effective in limiting platelet activation. A dysregulated adenosinergic axis appears to potentiate APS platelets for pro-thrombotic activation by aPL and other agonists. A dysregulated adenosinergic axis appears to potentiate APS platelets for pro-thrombotic activation by aPL and other agonists. We identified several mechanism-informed therapeutic targets, including FcgRIIa and PLC inhibitors, which prevent the shedding of CD73 from the platelet surface (Figure 1). Furthermore, both A2AR agonists and PDE3 inhibitors would appear to be useful strategies for restoring platelet homeostasis in APS, potentially with less risk of bleeding than more commonly used anti-platelet agents."

Cardiovascular • CD73 • SELP

CGS-21680 defers cisplatin-induced AKI-CKD transition in C57/BL6 mice. (PubMed, Chem Biol Interact) - "In conclusion, CGS-21680 could defer Cis-induced AKI-CKD transition via its vasodilatory, antioxidant, anti-inflammatory, and anti-fibrotic effects. Keywords: CGS-21680, Cisplatin, AKI-CKD transition, Vasodilation, Fibrosis."

Journal • Preclinical • Acute Kidney Injury • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • EDN1 • NOS3 • TGFB1 • TNFA

The different effects of four adenosine receptors in liver fibrosis. (PubMed, Front Pharmacol) - "Adenosine receptor agonists CCPA, CGS21680, BAY 60-6583, and namodenoson were used for A1R/A2AR/A2BR/A3R activation, respectively. Additionally, 5'-N-ethyl-carboxamidoadenosine (NECA), a metabolically stable adenosine analog, alleviated liver fibrosis and inhibited LX2 cell activity, proliferation, and migration. This study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • COL1A1

A2AR regulate inflammation through PKA/NF-κB signaling pathways in intervertebral disc degeneration. (PubMed, Eur J Med Res) - "The activation of A2AR can prevent inflammatory responses and mitigates degradation of IDD thus suggest a potential novel therapeutic strategy of IDD."

Journal • Back Pain • Inflammation • Lumbar Back Pain • Musculoskeletal Pain • Pain • ADORA2A • IL1B • IL6 • MMP3 • TNFA

Protective role of the CD73-A2AR axis in cirrhotic cardiomyopathy through negative feedback regulation of the NF-κB pathway. (PubMed, Front Immunol) - "Overexpression of CD73 in the myocardium via AAV9 injection and stimulation of A2AR with CGS 21680 inhibited myocardial inflammation and cardiomyocyte apoptosis induced by cirrhosis. Additionally, overexpression of CD73 suppressed the activation of the NF-κB pathway by upregulating the expression of the adenosine receptor A2A. Our study reveals that the CD73/A2AR signaling axis mitigates myocardial inflammation and apoptosis induced by cirrhosis through negative feedback regulation of the NF-κB pathway."

Journal • Cardiomyopathy • Cardiovascular • Fibrosis • Hepatology • Immunology • Inflammation • CD73 • NT5E

Adenosine A2A receptor as a potential regulator of Mycobacterium leprae survival mechanisms: new insights into leprosy neural damage. (PubMed, Front Pharmacol) - "On the other hand, activation of A2AR with its selective agonist, CGS21680, resulted in: 1) reduced lipid droplets accumulation and pro-lipogenic gene expression; 2) reduced production of IL-6 and IL-8; 3) reduced intracellular M. leprae viability; 4) increased levels of p-CREB. These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that M. leprae, by downmodulating the expression and activity of A2AR in Schwann cells, decreases A2AR downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus."

Journal • CNS Disorders • Infectious Disease • Metabolic Disorders • ADORA2A • CD73 • CXCL8 • IL6

Adenosine A2A receptor activation regulates the M1 macrophages activation to initiate innate and adaptive immunity in psoriasis. (PubMed, Clin Immunol) - "In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • ADORA2A • CXCL10 • IL23A • KRT16

An agonist of the adenosine A2A receptor, CGS21680, promotes corneal epithelial wound healing via the YAP signalling pathway. (PubMed, Br J Pharmacol) - "A2AR activation promotes wound healing by enhancing cellular proliferation and migration through the YAP signalling pathway. A2ARs play an important role in the maintenance of corneal epithelium integrity and may represent a novel therapeutic target for facilitating corneal epithelial wound healing."

Journal • Corneal Abrasion • ADORA2A

Cannabidiol at Nanomolar Concentrations Negatively Affects Signaling through the Adenosine A Receptor. (PubMed, Int J Mol Sci) - "However, CBD reduced the effect of the selective A receptor agonist, CGS 21680, on G-coupling and on the activation of the mitogen activated kinase signaling pathway. It is suggested that CBD is a negative allosteric modulator of the A receptor."

Journal

Adenosine receptors are novel regulators of human sebocyte biology (ISDS 2023) - "Importantly, the A2A agonist CGS 21680 slightly, but significantly decreased basal sebaceous lipogenesis (24- and 48-hr treatments; Nile Red), and could also suppress the lipogenic effect of the “acne-mimicking” inflammatory lipid mediator arachidonic acid (48-hr treatments; Nile Red)...Taken together, our data indicate that several adenosine receptors are expressed on human sebocytes. These receptors differentially influence sebocyte biology, and activation of A2A receptor appears to exert promising anti-acne effects in our in vitro model systems."

IO biomarker • Acne Vulgaris • Inflammation • ADORA2A • TLR4

Adenosine A receptors in the rostral ventrolateral medulla participate in blood pressure decrease with electroacupuncture in hypertensive rats. (PubMed, Front Cardiovasc Med) - "Activation of rVLM AR in DSHRs treated with sham-EA by an AR agonist, CGS-21680 (0.4 mM in 50 nl; n = 8), decreased BP...The AR level in the rVLM after EA was increased compared to the sham-EA and untreated DSHRs (n = 5 in each group; all P < 0.05). These data suggest that a 4-week twice weekly EA treatment reduced BP in salt-sensitive hypertensive rats likely through adenosine-mediated AR in the rVLM."

Journal • Preclinical • Anesthesia • Cardiovascular • Hypertension

Adenosine A receptors control generalization of contextual fear in rats. (PubMed, Transl Psychiatry) - "Conversely, AR activation with CGS21680 decreased fear generalization. Ex vivo electrophysiological recordings of field excitatory post-synaptic potentials (fEPSPs) in CA3-CA1 synapses and of population spikes in the lateral amygdala (LA), showed that the effect of SCH58261 is associated with a reversion of fear conditioning-induced decrease of long-term potentiation (LTP) in the dorsal hippocampus (DH) and with increased amplitude of LA LTP in conditioned animals. These data suggest that AR are engaged during contextual fear consolidation, controlling long-term potentiation mechanisms in both DH and LA during fear consolidation, impacting on fear generalization; this supports targeting AR during fear consolidation to control aberrant fear processing in PTSD and other fear-related disorders."

Journal • Preclinical • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • CA3

Functional Interaction between Adenosine A and mGlu Receptors Mediates STEP Phosphatase Activation and Promotes STEP/mGluR Binding in Mouse Hippocampus and Neuroblastoma Cell Line. (PubMed, Biomolecules) - "Indeed, the AR agonist CGS 21680 significantly increased STEP activity, and this effect was prevented not only by the AR antagonist ZM 241385, as expected, but also by the mGluR antagonist MPEP. In addition, we found that mGluR agonist DHPG-induced STEP activation was reversed not only by the mGluR antagonist MPEP but also by ZM 241385. Finally, via co-immunoprecipitation experiments, we found that mGluR and STEP physically interact when both receptors are activated (4) These results demonstrated a close functional interaction between mGlu and A receptors in the modulation of STEP activity."

Journal • Preclinical • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor

Caffeine exacerbates seizure-induced death via postictal hypoxia. (PubMed, Sci Rep) - "The administration of the non-selective A/A antagonist caffeine or the selective A agonist N6-cyclopentyladenosine reveals a detrimental effect on postictal hypoxia, providing support for caffeine modulating cerebral vasculature leading to brainstem hypoxia and cessation of breathing. Conversely, A activation with CGS-21680 was found to increase the lifespan of mice in both our models of seizure-induced death."

Journal • CNS Disorders • Epilepsy

Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats. (PubMed, Aging Dis) - "To tackle this issue, we administered CGS21680, a specific adenosine A2A subtype receptor agonist, intranasally twice a day for 7 days...Our findings suggest a critical role of pericyte dysfunction in WMLs and cognitive impairment within the rat VCI model. This insight contributes to our understanding of pathogenesis and offers prospects for targeted intervention in VCI."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Developmental Disorders • Vascular Neurology