Pharmacology of Adenosine Receptors: The State of the Art

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(3), P. 1591 - 1625

Published: May 31, 2018

Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A1, A2A, A2B, and A3. Due to rapid generation adenosine from cellular metabolism, widespread distribution its receptor subtypes in almost all organs tissues, this nucleoside induces multitude physiopathological effects, regulating central nervous, cardiovascular, peripheral, immune systems. It becoming clear that expression patterns receptors vary among cell types, lending weight idea they may be both markers pathologies useful targets for novel drugs. This review offers an overview current knowledge on receptors, including their characteristic structural features, molecular interactions functions, as well essential roles pain, cancer, neurodegenerative, inflammatory, autoimmune diseases. Finally, we highlight latest findings molecules capable targeting report which stage drug development have reached.

Language: Английский

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Methotrexate and its mechanisms of action in inflammatory arthritis

Nature Reviews Rheumatology, Journal Year: 2020, Volume and Issue: 16(3), P. 145 - 154

Published: Feb. 17, 2020

Language: Английский

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Methotrexate an Old Drug with New Tricks

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(20), P. 5023 - 5023

Published: Oct. 10, 2019

Methotrexate (MTX) is the first line drug for treatment of a number rheumatic and non-rheumatic disorders. It currently used as an anchor disease, modifying anti-rheumatic in rheumatoid arthritis (RA). Despite development numerous new targeted therapies, MTX remains backbone RA therapy due to its potent efficacy tolerability. There has been also growing interest use chronic viral mediated arthritis. Many viruses—including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, human immunodeficiency virus—have associated with arthritogenic diseases reminiscent RA. may provide benefits although potential risk attenuating patients’ immune surveillance capacities. In this review, we describe emerging mechanisms action anti-inflammatory complementing well-established immunomodulatory activity. The involve adenosine signaling modulation, alteration cytokine networks, generation reactive oxygen species HMGB1 alarmin suppression. We comprehensive understanding toxic effects. Lastly, discussed efficacy, well safety, management viral-related syndromes.

Language: Английский

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Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: June 6, 2019

T cells play a critical role in cancer control, but range of potent immunosuppressive mechanisms can be upregulated the tumor microenvironment (TME) to abrogate their activity. While various immunotherapies (IMTs) aiming at re-invigorating T-cell-mediated anti-tumor response, such as immune checkpoint blockade (ICB), and adoptive cell transfer (ACT) natural or gene-engineered ex vivo expanded tumor-specific cells, have led unprecedented clinical responses, only small proportion patients benefit from these treatments. Important research efforts are thus underway identify biomarkers well develop personalized combinatorial approaches that target other inhibitory TME. In recent years, adenosinergic signaling has emerged powerful immuno-metabolic tumors. Like several barriers TME, PD-1/PDL-1 axis, CTLA-4, indoleamine 2,3-dioxygenase (IDO-1), adenosine plays important physiologic roles, been co-opted by tumors promote growth impair immunity. Several agents counteracting axis developed, pre-clinical studies demonstrated activity, alone combination with IMTs including ICB ACT. Here we review regulation levels which it promotes broadly suppresses protective immunity, extra focus on attenuation function. Finally, present an overview promising being explored for blocking enhanced control solid

Language: Английский

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Methotrexate mechanism in treatment of rheumatoid arthritis

Joint Bone Spine, Journal Year: 2018, Volume and Issue: 86(3), P. 301 - 307

Published: Aug. 3, 2018

Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often first line medication for RA treatment. In review, we examine multiple hypotheses explain mechanism methotrexate efficacy RA. These include folate antagonism, adenosine signaling, generation reactive oxygen species (ROS), decrease adhesion molecules, alteration cytokine profiles, polyamine inhibition amongst some others. Currently, signaling probably most widely accepted explanation given that increases levels on engagement with its extracellular receptors an intracellular cascade activated promoting overall anti-inflammatory state. addition these hypotheses, from perspective adverse effects consider newer genetic markers toxicity Lastly, briefly discuss additive setting TNF-α inhibitor Ultimately, finding a clear pathway leading RA, there may be way formulate more potent therapies fewer side effects.

Language: Английский

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Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: March 28, 2019

Adenosine receptors (ARs) function in the body's response to conditions of pathology and stress associated with a functional imbalance, such as supply demand energy/oxygen/nutrients. Extracellular adenosine concentrations vary widely raise or lower basal activation four subtypes ARs. Endogenous can correct an energy imbalance during hypoxia other stress, for example, by slowing heart rate A1AR increasing blood muscle A2AAR. Moreover, exogenous AR agonists, antagonists, allosteric modulators be applied therapeutic benefit, medicinal chemists working toward that goal have reported thousands agents. Thus, numerous clinical trials ensued, using promising agents modulate adenosinergic signaling, most which not succeeded. Currently, short-acting, parenteral Regadenoson, are only agonists approved human use. However, new concepts compounds currently being developed preclinical evaluation, initial results encouraging. This review focuses on key positive (PAMs) disease treatment diagnosis. treating inflammation, pain, cancer, nonalcoholic steatohepatitis, angina, sickle cell disease, ischemic diabetes been under development. Multiple two A3AR ongoing

Language: Английский

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Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: April 23, 2019

Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation neutrophils, and this has been proposed to regulate NETosis some contexts. Here we report that selective agonism the A2A receptor (CGS21680) suppresses aPL Ab-mediated protein kinase A-dependent fashion. CGS21680 also reduces thrombosis inferior vena cavae both control mice administered Abs. The antithrombotic medication dipyridamole known potentiate signaling increasing concentrations interfering breakdown cAMP. Like CGS21680, via mitigates venous mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm APS, may extend disease general population.

Language: Английский

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Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Aug. 17, 2022

Abstract The discovery of immune checkpoint inhibitors (ICIs) has now been universally acknowledged as a significant breakthrough in tumor therapy after the targeted treatment molecules: anti-programmed cell death protein 1/programmed ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on several cancer types achieved satisfying results. However, there are still quite lot patients suffering from severe side effects ineffective outcomes. Although current ICI is far satisfying, series novel molecules with remarkable preclinical clinical benefits being widely investigated, like V-domain Ig suppressor activation (VISTA), which can also be called PD-1 homolog (PD-1H), ectonucleotidases: CD39, CD73, CD38, belong to ribosyl cyclase family, etc. In this review, we systematically summarized discussed these molecules' biological structures, molecular features, corresponding drugs, aiming help in-depth understanding promote practice therapy.

Language: Английский

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Adenosine and Inflammation: Here, There and Everywhere

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(14), P. 7685 - 7685

Published: July 19, 2021

Adenosine is a ubiquitous endogenous modulator with the main function of maintaining cellular and tissue homeostasis in pathological stress conditions. It exerts its effect through interaction four G protein-coupled receptor (GPCR) subtypes referred as A1, A2A, A2B, A3 adenosine receptors (ARs), each which has unique pharmacological profile distribution. potent inflammation, for this reason adenosinergic system represents an excellent target myriad diseases inflammation cause, pathogenetic mechanism, consequence, manifestation, or protective factor. The omnipresence ARs every cell immune well almost all cells body both opportunity obstacle to clinical use AR ligands. This review offers overview cardinal role modulation showing how stimulation blocking agents capable regulating extracellular concentration can represent promising therapeutic strategies treatment chronic inflammatory pathologies, neurodegenerative diseases, cancer.

Language: Английский

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International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(2), P. 340 - 372

Published: March 17, 2022

Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature classification adenosine receptors (2011) contained a number emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, oligomerization, diversity, allosteric modulation by small molecules. Since then, wealth new data results has been added, allowing us explore novel concepts such as target binding kinetics biased signaling receptors, examine multitude structures ligands, gauge pharmacology, evaluate clinical trials ligands. This review should therefore be considered further update our reports from 2001 2011.

Significance Statement

Adenosine (ARs) are continuing interest for future treatment chronic acute disease conditions, inflammatory diseases, neurodegenerative afflictions, cancer. The design AR agonists ("biased" or not) antagonists is largely structure based now, thanks tremendous progress in structural biology. A_2A- A_2BAR appear modulate immune response tumor Many indication ongoing, whereas an A_2AAR antagonist (istradefylline) approved anti-Parkinson agent.

Language: Английский

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