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Kenneth A. Jacobson - One of the best experts on this subject based on the ideXlab platform.
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international union of basic and clinical pharmacology lxxxi nomenclature and classification of Adenosine Receptors an update
Pharmacological Reviews, 2011Co-Authors: Bertil B. Fredholm, Adriaan P. Ijzerman, Kenneth A. Jacobson, Joel Linden, Christa E MullerAbstract: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 as therapeutic targets
Nature Reviews Drug Discovery, 2006Co-Authors: Kenneth A. Jacobson, Zhan-guo GaoAbstract:Adenosine Receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of Adenosine Receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various Adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of Adenosine receptor modulators considerably closer. Modulation of Adenosine Receptors (ARs) using selective agonists and antagonists is a promising therapeutic strategy for the treatment of diseases and disorders of the cardiovascular, renal and nervous systems, as well as endocrine and pulmonary disorders. Although the development of novel AR ligands has therefore been the focus of much research, so far none has been approved for clinical use, in part owing to the ubiquity of ARs and the consequent possibility of side effects. However, there has been a recent impetus towards novel clinical targets, stimulated by the discovery and elucidation of the roles of the various AR subtypes and Adenosine. The A_1, A_2A, A_2B and A_3 are the four known subtypes of Adenosine Receptors (ARs). All four subtypes are members of the superfamily of G-protein-coupled Receptors, and each of these ARs has a unique pharmacological profile, tissue distribution and effector coupling. Classically, AR signalling is thought to occur through inhibition or stimulation of adenylyl cyclase (also known as adenylate cyclase). However, it is now apparent that other pathways, such as phospholipase C, Ca^2+ and mitogen-activated protein kinases, are also relevant. Modification of Adenosine has been the key strategy for discovering AR agonists and the structure–activity relationships of Adenosine at ARs have been extensively probed. Highly selective agonists of the different ARs have been designed through both empirical approaches and a semi-rational approach based on molecular modelling. Adenosine Receptors have been implicated in the aetiology of various cardiovascular, inflammatory and neurological diseases. Jacobson and Gao review the development and therapeutic promise of agonists and antagonists with high selectivity for each of the four Adenosine receptor subtypes.
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Adenosine Receptors as therapeutic targets
Nature Reviews Drug Discovery, 2006Co-Authors: Kenneth A. Jacobson, Zhan-guo GaoAbstract:Adenosine Receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of Adenosine Receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various Adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of Adenosine receptor modulators considerably closer.
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Interactions of flavones and other phytochemicals with Adenosine Receptors.
Advances in experimental medicine and biology, 2002Co-Authors: Kenneth A. Jacobson, Stefano Moro, John A. Manthey, Patrick L. WestAbstract:Dietary flavonoids have varied effects on animal cells, such as inhibition of platelet binding and aggregation, inhibition of inflammation, and anticancer properties, but the mechanisms of these effects remain largely unexplained. Adenosine Receptors are involved in the homeostasis of the immune, cardiovascular, and central nervous systems, and Adenosine agonists/antagonists exert many similar effects. The affinity of flavonoids and other phytochemicals to Adenosine Receptors suggests that a wide range of natural substances in the diet may potentially block the effects of endogenous Adenosine. We used competitive radioligand binding assays to screen flavonoid libraries for affinity and a computational CoMFA analysis of flavonoids to compare steric and electrostatic requirements for ligand recognition at three subtypes of Adenosine Receptors. Flavone derivatives, such as galangin, were found to bind to three subtypes of Adenosine Receptors in the µM range. Pentamethylmorin (Ki 2.65 µM) was 14- to 17-fold selective for human A3, Receptors than for A1, and A2A Receptors. An isoflavone, genistein, was found to bind to A1, Receptors. Aurones, such as hispidol (Ki 350 nM) are selective A1, receptor antagonists, and, like genistein, are present in soy. The flavones, chemically optimized for receptor binding, have led to the antagonist, MRS 1067 (3,6-dichloro-2’-(isopropoxy)-4’-methylflavone), which is 200-fold more selective for human A3 than A1, Receptors. Adenosine receptor antagonism, therefore, may be important in the spectrum of biological activities reported for the flavonoids.
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The role of Adenosine Receptors in the central action of caffeine
Pharmacopsychoecologia, 1994Co-Authors: J. W. Daly, Dan Shi, Olga Nikodijevic, Kenneth A. JacobsonAbstract:The behavioral effects of caffeine appear likely to be due in large measure to antagonism of the action of endogenous Adenosine at A1- and A2a-Receptors in the central nervous system. Other biochemical mechanisms of action of caffeine, such as release of intracellular calcium, inhibition of phosphodiesterases and blockade of regulatory sites of GABAA-reccptors, would require much higher concentrations than the micromolar concentrations of caffeine associated with behavioral stimulation. However, micromolar concentrations of caffeine also would be expected to cause only a modest blockade of Adenosine Receptors. Selective Adenosine agonists and xanthine antagonists have provided some insights into central roles for Adenosine receptor subtypes. Thus, behavioral stimulation by xanthines appears to require blockade of both A1- and A2a-Receptors. Chronic blockade of Adenosine Receptors by caffeine would be expected to result in alterations in the central Receptors and pathways that are regulated by Adenosine through A1- and A2a-Receptors. Indeed, chronic caffeine docs alter the density not only of Adenosine Receptors, but also of adrenergic, cholinergic, GABAergic and serotonergic Receptors. Behavioral responses to agents acting through dopaminergic and cholinergic pathways arc altered. As yet, a coherent explanation of the acute and chronic effects of caffeine in terms of blockade of Adenosine Receptors has not emerged. Interactions between pathways subserved by A1 - and A2a-adcnosine Receptors complicate attempts to interpret caffeine pharmacology, as does the complex control by Adenosine Receptors of dopamincrgic, cholinergic and other central pathways.
Bertil B. Fredholm - One of the best experts on this subject based on the ideXlab platform.
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Adenosine Receptors as drug targets — what are the challenges?
Nature reviews. Drug discovery, 2013Co-Authors: Jiangfan Chen, Holger K. Eltzschig, Bertil B. FredholmAbstract:Adenosine signalling has long been a target for drug development, with Adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at Adenosine Receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of Adenosine Receptors. There is strong evidence that Adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual Adenosine Receptors — either directly or indirectly — have now entered the clinic. However, only one Adenosine receptor-specific agent — the Adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of Adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting Adenosine Receptors and discuss strategies to overcome these challenges.
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international union of basic and clinical pharmacology lxxxi nomenclature and classification of Adenosine Receptors an update
Pharmacological Reviews, 2011Co-Authors: Bertil B. Fredholm, Adriaan P. Ijzerman, Kenneth A. Jacobson, Joel Linden, Christa E MullerAbstract: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 as drug targets
Experimental Cell Research, 2010Co-Authors: Bertil B. FredholmAbstract:Abstract There are four Adenosine Receptors, A1, A2A, A2B and A3, together forming a defined subgroup of G protein coupled Receptors. They are well conserved and widely expressed. The endogenous agonist, Adenosine, has a minimal concentration in body fluids (20–200 nM) that is sufficient to slightly activate the Receptors where they are very highly expressed—as in the basal ganglia, on fat cells and in the kidney. Here Adenosine can play a physiological role and here antagonists such as caffeine can have effects in healthy individuals. Adenosine levels rise in stress and distress (up to 30 μM in ischemia) and tend to minimize the risk for adverse outcomes by increasing energy supply and decreasing cellular work, by stimulating angiogenesis, mediating preconditioning and having multiple effects on immune competent cells. These pathophysiological roles of Adenosine also offer some potential drug targets, but the fact that Adenosine Receptors are involved in so many processes does not simplify drug development.
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Modulation of glial cell functions by Adenosine Receptors.
Physiology & Behavior, 2007Co-Authors: Elisabetta Daré, Gunnar Schulte, Olga Karovic, Christian Hammarberg, Bertil B. FredholmAbstract:Abstract DARE E, SCHULTE G, KAROVIC O, HAMMARBERG C, FREDHOLM BB. Modulation of glial cell functions by Adenosine Receptors. PHYSIOL. BEHAV. 000-000, 2006. Adenosine is an endogenous neuromodulator, acting on four distinctive G-protein-coupled Receptors, the A 1 , A 2A , A 2B and A 3 Adenosine Receptors. Increased neuronal activity and, hypoxia or ischemia, result in elevated levels of Adenosine reflecting changes of the metabolic state. This increases activation of the Adenosine Receptors. It is well appreciated that Adenosine has a neuroprotective role in brain injuries. Although Adenosine effects have been explained mainly by actions on nerve cells, modulation of glial functions by Adenosine is likely to be important as discussed in this minireview. Thus, in astrocytes Adenosine Receptors modulate inter alia glycogen metabolism, glutamate transporters, astrogliosis and astrocyte swelling. Microglial cells appear to be important in regulating Adenosine formation from ATP and Adenosine can affect many microglial signaling pathways. Adenosine Receptors on oligodendrocytes regulate white matter development.
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Modulation of glial cell functions by Adenosine Receptors.
Physiology & behavior, 2007Co-Authors: Elisabetta Daré, Gunnar Schulte, Olga Karovic, Christian Hammarberg, Bertil B. FredholmAbstract:Adenosine is an endogenous neuromodulator, acting on four distinctive G-protein-coupled Receptors, the A1, A2A, A2B and A3 Adenosine Receptors. Increased neuronal activity and, hypoxia or ischemia, result in elevated levels of Adenosine reflecting changes of the metabolic state. This increases activation of the Adenosine Receptors. It is well appreciated that Adenosine has a neuroprotective role in brain injuries. Although Adenosine effects have been explained mainly by actions on nerve cells, modulation of glial functions by Adenosine is likely to be important as discussed in this minireview. Thus, in astrocytes Adenosine Receptors modulate inter alia glycogen metabolism, glutamate transporters, astrogliosis and astrocyte swelling. Microglial cells appear to be important in regulating Adenosine formation from ATP and Adenosine can affect many microglial signaling pathways. Adenosine Receptors on oligodendrocytes regulate white matter development.
Christa E Muller - One of the best experts on this subject based on the ideXlab platform.
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international union of basic and clinical pharmacology lxxxi nomenclature and classification of Adenosine Receptors an update
Pharmacological Reviews, 2011Co-Authors: Bertil B. Fredholm, Adriaan P. Ijzerman, Kenneth A. Jacobson, Joel Linden, Christa E MullerAbstract: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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Development of Spin-Labeled Probes for Adenosine Receptors†
Journal of medicinal chemistry, 2005Co-Authors: Janez Ilaš, Slavko Pečar, Jörg Hockemeyer, Harald Euler, And Armin Kirfel, Christa E MullerAbstract:Functionalized xanthine derivatives bearing a nitroxide moiety at the 3- or 8-position were synthesized as electron paramagnetic resonance (EPR) probes. The 8-cyclopentyl-1-propylxanthine derivative 4, spin-labeled at N3 by substitution with a nitroxide-bearing dihydropyrrole moiety, was a potent and selective A(1) Adenosine receptor antagonist (K(i) for A(1) 5.5 nM, 1600-fold selectivity vs A(2A), >200-fold vs A(2B), and 310-fold vs A(3) Adenosine Receptors). 8-(1-Oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)-1,3-dipropylxanthine 10 (K(i) for A(1) 8.2 nM) was similarly potent and selective, while 8-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)-1,3-dipropylxanthine 11 (K(i) for A(1) 160 nM) exhibited significantly lower affinity for A(1) Adenosine Receptors. 8-[4-(((1-Oxyl-2,2,6,6-tetramethylpiperidin-4-yl)amino)-2-oxoethoxy)phenyl]-1-propylxanthine14, a 3-unsubstituted xanthine derivative, was found to be a potent A(2B) Adenosine receptor antagonist (K(i) for A(2B) 48 nM) but also exhibited high affinity for A(1) Receptors (K(i) for A(1) 15.7 nM). An X-ray structure of compound 10 was obtained, confirming the proposed structure. The novel spin-labeled A(1)-selective or A(1)/A(2B)-nonselective Adenosine receptor antagonists may become useful probes for biophysicochemical investigations of Adenosine Receptors in their membrane environment.
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synthesis of paraxanthine analogs 1 7 disubstituted xanthines and other xanthines unsubstituted at the 3 position structure activity relationships at Adenosine Receptors
Journal of Medicinal Chemistry, 1993Co-Authors: Christa E Muller, Dan Shi, M Manning, John W DalyAbstract:Synthetic procedures for the preparation of various 3-unsubstituted xanthines, including paraxanthine analogs (1,7-disubstituted xanthines) and 1,8-disubstituted xanthines, were developed. Silylation of 1-substituted xanthines followed by alkylation at the 7-position provides a facile route to paraxanthine analogs. Regioselective alkylation of tris(trimethylsilyl)-6-aminouracil provides 3-substituted 6-aminouracils, which are converted to 1,8-disubstituted xanthines by standard procedures. The ring closure of 3-substituted 5-cyclopentanecarboxamido- and 5-(benzoylamino)-6-aminouracils requires drastic reaction conditions. Affinity for brain A1 and A2 Adenosine Receptors was determined in binding assays for these and other xanthines with substituents in 1-, 3-, 7-, 8-, and 9-positions. Substitution at the 1-position was necessary for high affinity at Adenosine Receptors. 1,3-Disubstituted xanthines generally had higher affinity than 1,7-disubstituted xanthines. 1,8-Disubstituted xanthines had high affinity for Adenosine Receptors; some were highly selective for A1 Receptors.
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effect of trifluoromethyl and other substituents on activity of xanthines at Adenosine Receptors
Journal of Medicinal Chemistry, 1993Co-Authors: Kenneth A. Jacobson, Christa E Muller, Dan Shi, John W Daly, Carola Gallorodriguez, Malcolm Manning, John L Neumeyer, Leonidas Kiriasis, Wolfgang PfleidererAbstract:An aryl p-(trifluoromethyl) substituent increases the affinity of 1,3-disubstituted 8-phenylxanthines at A2a-Adenosine Receptors, while having little effect on affinity at A1-Adenosine Receptors. In contrast, an aryl p-(trifluoromethyl) substituent has little effect on affinity of 3,7-disubstituted and 1,3,7-trisubstituted 8-phenylxanthines. An aryl p-sulfo substituent reduces affinity of all 8-phenylxanthines at A1- and A2a-Adenosine Receptors. An 8-(trifluoromethyl) substituent markedly reduces affinity of 1,3-dialkylxanthines at both A1- and A2a-Adenosine Receptors. In contrast, 8-(trifluoromethyl)caffeine retains affinity for A2a-Adenosine Receptors, but does lose affinity for A1-Adenosine Receptors. 8-Bromo-, 8-acryl-, and 8-pent-1-enylcaffeines are also selective for A2-Adenosine Receptors, while 8-cyclobutylcaffeine is nonselective. 8-[trans-2-(tert-butyloxycarbonyl)vinylcaffeine is 20-fold selective for Aza vs A1 Receptors.
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Adenosine Receptors and their modulators.
Pharmaceutica acta Helvetiae, 1993Co-Authors: Christa E Muller, Thomas SciorAbstract:Abstract The identification and characterization of Adenosine Receptors and the development of potent, receptor subtype-selective agonist and antagonists has been an active area of research for the past 20 years. Major recent advances in the field have been the cloning of several Adenosine receptor subtypes of different species, including the discovery of a new subtype, designated A3, the discovery and development of new agonists and antagonists particularly those with selectivity for the A2a Adenosine receptor, the characterization of signal transduction pathways, and the development of agents which act indirectly on the Adenosine receptor system. The present article focusses on aspects of pharmaceutical/medicinal chemistry related to Adenosine Receptors.
Zhan-guo Gao - One of the best experts on this subject based on the ideXlab platform.
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Adenosine Receptors as therapeutic targets
Nature Reviews Drug Discovery, 2006Co-Authors: Kenneth A. Jacobson, Zhan-guo GaoAbstract:Adenosine Receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of Adenosine Receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various Adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of Adenosine receptor modulators considerably closer. Modulation of Adenosine Receptors (ARs) using selective agonists and antagonists is a promising therapeutic strategy for the treatment of diseases and disorders of the cardiovascular, renal and nervous systems, as well as endocrine and pulmonary disorders. Although the development of novel AR ligands has therefore been the focus of much research, so far none has been approved for clinical use, in part owing to the ubiquity of ARs and the consequent possibility of side effects. However, there has been a recent impetus towards novel clinical targets, stimulated by the discovery and elucidation of the roles of the various AR subtypes and Adenosine. The A_1, A_2A, A_2B and A_3 are the four known subtypes of Adenosine Receptors (ARs). All four subtypes are members of the superfamily of G-protein-coupled Receptors, and each of these ARs has a unique pharmacological profile, tissue distribution and effector coupling. Classically, AR signalling is thought to occur through inhibition or stimulation of adenylyl cyclase (also known as adenylate cyclase). However, it is now apparent that other pathways, such as phospholipase C, Ca^2+ and mitogen-activated protein kinases, are also relevant. Modification of Adenosine has been the key strategy for discovering AR agonists and the structure–activity relationships of Adenosine at ARs have been extensively probed. Highly selective agonists of the different ARs have been designed through both empirical approaches and a semi-rational approach based on molecular modelling. Adenosine Receptors have been implicated in the aetiology of various cardiovascular, inflammatory and neurological diseases. Jacobson and Gao review the development and therapeutic promise of agonists and antagonists with high selectivity for each of the four Adenosine receptor subtypes.
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Adenosine Receptors as therapeutic targets
Nature Reviews Drug Discovery, 2006Co-Authors: Kenneth A. Jacobson, Zhan-guo GaoAbstract:Adenosine Receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of Adenosine Receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various Adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of Adenosine receptor modulators considerably closer.
Bruce N. Cronstein - One of the best experts on this subject based on the ideXlab platform.
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Adenosine and Adenosine Receptors in the pathogenesis and treatment of rheumatic diseases
Nature Reviews Rheumatology, 2016Co-Authors: Bruce N. Cronstein, Michail V. SitkovskyAbstract:Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface Receptors. The expression and function of Adenosine Receptors on different cell types change during the course of rheumatic diseases, such as rheumatoid arthritis (RA). Targeting Adenosine Receptors directly for the treatment of rheumatic diseases is currently under study; however, indirect targeting of Adenosine Receptors by enhancing Adenosine levels at inflamed sites accounts for most of the anti-inflammatory effects of methotrexate, the anchor drug for the treatment of RA. In this Review, we discuss the regulation of extracellular Adenosine levels and the role of Adenosine in regulating the inflammatory and immune responses in rheumatic diseases such as RA, psoriasis and other types of inflammatory arthritis. In addition, Adenosine and its Receptors are involved in promoting fibrous matrix production in the skin and other organs, and the role of Adenosine in fibrosis and fibrosing diseases is also discussed.
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The roles of Adenosine and Adenosine Receptors in bone remodeling.
Frontiers in Bioscience, 2011Co-Authors: Bruce N. CronsteinAbstract:Adenosine regulates a wide variety of physiological processes including heart rate, vasodilation and inflammation through the activation of specific cell surface Adenosine Receptors. In addition to these well-established roles of Adenosine, recent genetic and pharmacological research has implicated Adenosine as an important regulator in bone remodeling. The secretion of Adenosine and the presence of its four Receptors in bone cells have been well documented. More recently, we provided the first evidence that Adenosine regulates osteoclast formation and function through A1 receptor (A1R), and showed that A1R-knockout mice have significantly increased bone volume as a result of impaired osteoclast-mediated bone resorption. Moreover, Adenosine A1R-knockout mice are protective from boss loss following ovariectomy further supporting the involvement of Adenosine in osteoclast formation and function. This short review summarizes current knowledge related to the roles of Adenosine and Adenosine Receptors in bone formation and remodeling. A deeper insight into the regulation of bone metabolism by Adenosine Receptors should assist in developing new therapies for osteoporosis.
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Adenosine Receptors: Therapeutic Aspects for Inflammatory and Immune Diseases - Adenosine Receptors: therapeutic aspects for inflammatory and immune diseases
Nature reviews. Drug discovery, 2008Co-Authors: György Haskó, Bruce N. Cronstein, Joel Linden, Pal PacherAbstract: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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Adenosine Receptors therapeutic aspects for inflammatory and immune diseases
Nature Reviews Drug Discovery, 2006Co-Authors: György Haskó, Bruce N. Cronstein, Joel Linden, Pal PacherAbstract: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.