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Adenosine Receptors
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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.
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.
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.