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      Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

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          Abstract

          Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A 1AR, A 2AAR, A 2BAR, and A 3AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A 1AR and A 2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A 2BAR and A 3AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.

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          Most cited references306

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          International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update.

          In the 10 years since our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors, no developments have led to major changes in the recommendations. However, there have been so many other developments that an update is needed. The fact that the structure of one of the adenosine receptors has recently been solved has already led to new ways of in silico screening of ligands. The evidence that adenosine receptors can form homo- and heteromultimers has accumulated, but the functional significance of such complexes remains unclear. The availability of mice with genetic modification of all the adenosine receptors has led to a clarification of the functional roles of adenosine, and to excellent means to study the specificity of drugs. There are also interesting associations between disease and structural variants in one or more of the adenosine receptors. Several new selective agonists and antagonists have become available. They provide improved possibilities for receptor classification. There are also developments hinting at the usefulness of allosteric modulators. Many drugs targeting adenosine receptors are in clinical trials, but the established therapeutic use is still very limited.
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            Adenosine receptors: therapeutic aspects for inflammatory and immune diseases.

            Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.
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              Immunity, inflammation and cancer: a leading role for adenosine.

              Cancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in regulating the complex interplay among immune, inflammatory, endothelial and cancer cells during the course of neoplastic disease.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                24 March 2020
                March 2020
                : 9
                : 3
                : 785
                Affiliations
                [1 ]Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; wisepulmo@ 123456gmail.com (W.I.E.); kkoba@ 123456med.kobe-u.ac.jp (K.K.); nishiy@ 123456med.kobe-u.ac.jp (Y.N.)
                [2 ]Department of Pulmonology and Respiratory Medicine, Medical Faculty of Airlangga University, Surabaya 60131, Indonesia
                Author notes
                [* ]Correspondence: tnagano@ 123456med.kobe-u.ac.jp ; Tel.: +81-78-382-5660; Fax: +81-78-382-5661
                Author information
                https://orcid.org/0000-0003-0790-5139
                Article
                cells-09-00785
                10.3390/cells9030785
                7140859
                32213945
                d034f654-500b-4606-aacc-d7f8fbd13f03
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 February 2020
                : 23 March 2020
                Categories
                Review

                adenosine,adenosine receptors,g protein-coupled receptors,agonists,antagonists,allosteric molecules

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