Recent developments in adenosine receptor ligands and their potential as novel drugs
TL;DR: Medicinal chemical approaches have been applied to all four of the adenosine receptor (AR) subtypes to create selective agonists and antagonists for each to facilitate research on therapeutic applications of modulating the ARs and in some cases has provided clinical candidates.
About: This article is published in Biochimica et Biophysica Acta.The article was published on 2011-05-01 and is currently open access. It has received 384 citations till now. The article focuses on the topics: Preladenant & Agonist.
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TL;DR: In the 10 years since the 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, but there have been so many other developments that an update is needed.
Abstract: 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.
1,145 citations
Cites background from "Recent developments in adenosine re..."
...Selective agonists and antagonists for all four adenosine receptor subtypes are available (Müller, 2000a,b; Yan et al., 2003; Jacobson and Gao, 2006; Müller and Ferré, 2007; Elzein and Zablocki, 2008; Müller and Jacobson, 2011)....
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TL;DR: The biology of adenosine signalling is focused on to identify hurdles in the development of additional pharmacological compounds targeting adenoine receptors and discuss strategies to overcome these challenges.
Abstract: 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.
730 citations
TL;DR: Insight into potential clinical application of adenosinergic and other purinergic‐targeting therapies and forecast how these might develop in combination with other anti‐cancer modalities are provided.
Abstract: Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection-type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized "immune checkpoint mediator" that interferes with anti-tumor immune responses. In this review, we focus on CD39 and CD73 ectoenzymes and encompass aspects of the biochemistry of these molecules as well as detailing the distribution and function on immune cells. Effects of CD39 and CD73 inhibition in preclinical and clinical studies are discussed. Finally, we provide insights into potential clinical application of adenosinergic and other purinergic-targeting therapies and forecast how these might develop in combination with other anti-cancer modalities.
576 citations
TL;DR: The raising of a mouse monoclonal antibody against human A2AAR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket is reported and results suggest a new strategy to modulate the activity of G-protein-coupled receptors.
Abstract: G-protein-coupled receptors are the largest class of cell-surface receptors, and these membrane proteins exist in equilibrium between inactive and active states. Conformational changes induced by extracellular ligands binding to G-protein-coupled receptors result in a cellular response through the activation of G proteins. The A(2A) adenosine receptor (A(2A)AR) is responsible for regulating blood flow to the cardiac muscle and is important in the regulation of glutamate and dopamine release in the brain. Here we report the raising of a mouse monoclonal antibody against human A(2A)AR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket, and describe the structure of A(2A)AR in complex with the antibody Fab fragment (Fab2838). This structure reveals that Fab2838 recognizes the intracellular surface of A(2A)AR and that its complementarity-determining region, CDR-H3, penetrates into the receptor. CDR-H3 is located in a similar position to the G-protein carboxy-terminal fragment in the active opsin structure and to CDR-3 of the nanobody in the active β(2)-adrenergic receptor structure, but locks A(2A)AR in an inactive conformation. These results suggest a new strategy to modulate the activity of G-protein-coupled receptors.
284 citations
Cites background from "Recent developments in adenosine re..."
...Strong epidemiological evidence indicates that coffee drinkers have a lower risk of Parkinson’s diseas...
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TL;DR: This review provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.
Abstract: The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.
251 citations
References
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Journal Article•
TL;DR: Experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions.
Abstract: Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.
2,582 citations
"Recent developments in adenosine re..." refers background in this paper
...Extracellular adenosine acts on a family of four cell surface receptors termed adenosine receptors (ARs) of which there exist four subtypes: A1, A2A, A2B, and A3 [1,2]....
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...The levels of extracellular adenosine can rise substantially in response to stress, such as hypoxic stress, and the resultant activation of ARs acts to adapt to the stress [1,2]....
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...32 [5 2] 32 ,8 00 ( h) 41 ,7 00 ( h) > 30 ,0 00 ( h) 0....
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...Novel 8-(furan-2-yl)-3-substituted thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-thione derivatives as potential adenosine A2A receptor antagonists....
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...in the heart or brain), inhibition of the release of excitotoxic neurotransmitters, suppression of cytokine-induced apoptosis, or reduced inflammatory response [1,2]....
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TL;DR: The crystal structure of the human A2A adenosine receptor is determined, in complex with a high-affinity subtype-selective antagonist, ZM241385, to 2.6 angstrom resolution and suggests a role for ZM 241385 in restricting the movement of a tryptophan residue important in the activation mechanism of the class A receptors.
Abstract: The adenosine class of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) mediates the important role of extracellular adenosine in many physiological processes and is antagonized by caffeine. We have determined the crystal structure of the human A2A adenosine receptor, in complex with a high-affinity subtype-selective antagonist, ZM241385, to 2.6 angstrom resolution. Four disulfide bridges in the extracellular domain, combined with a subtle repacking of the transmembrane helices relative to the adrenergic and rhodopsin receptor structures, define a pocket distinct from that of other structurally determined GPCRs. The arrangement allows for the binding of the antagonist in an extended conformation, perpendicular to the membrane plane. The binding site highlights an integral role for the extracellular loops, together with the helical core, in ligand recognition by this class of GPCRs and suggests a role for ZM241385 in restricting the movement of a tryptophan residue important in the activation mechanism of the class A receptors.
1,754 citations
"Recent developments in adenosine re..." refers background in this paper
...83 ( r) [ 63 ] > 1 00 0 (r ) [6 3]...
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...2-n-Butyl-9-methyl-8-[1,2,3]triazol-2yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists....
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...37 C P5 32 ,9 03 [ 10 3] 89 8 (m ) > 1 0, 00 0 (m ) > 10 ,0 00 ( m ) 9....
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...1 (h ) [3 2] > 10 ,0 00 ( h) [ 10 9] > 10 ,0 00 ( h) [ 10 9]...
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...6 n M ) [1 64 ] 28 ,0 00 ( r) [ 16 5] 54 ( r) [ 16 5] 82 00 [ 16 5] > 10 ,0 00 ( r) [ 13 3]...
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TL;DR: Recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, have brought the goal of therapeutic application of adenosines receptor modulators considerably closer.
Abstract: 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
1,303 citations
"Recent developments in adenosine re..." refers background in this paper
...A1 receptor antagonists—Various A1AR antagonists, xanthines and nonxanthines, have been or are currently being explored for clinical applications [109] for heart failure, and for improving renal function and treatment of acute renal failure....
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TL;DR: In the 10 years since the 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, but there have been so many other developments that an update is needed.
Abstract: 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.
1,145 citations
TL;DR: The A(1)R/D( 1)R heteromerization may be one molecular basis for the demonstrated antagonistic modulation of A(2)R of D(1]R receptor signaling in the brain and seems to be essential for the blockade of A-1-R agonist-induced A(3)R-induced coclustering and for the desensitization of the D(0)R agonists cAMP accumulation.
Abstract: The possible molecular basis for the previously described antagonistic interactions between adenosine A(1) receptors (A(1)R) and dopamine D(1) receptors (D(1)R) in the brain have been studied in mouse fibroblast Ltk(-) cells cotransfected with human A(1)R and D(1)R cDNAs or with human A(1)R and dopamine D(2) receptor (long-form) (D(2)R) cDNAs and in cortical neurons in culture. A(1)R and D(1)R, but not A(1)R and D(2)R, were found to coimmunoprecipitate in cotransfected fibroblasts. This selective A(1)R/D(1)R heteromerization disappeared after pretreatment with the D(1)R agonist, but not after combined pretreatment with D(1)R and A(1)R agonists. A high degree of A(1)R and D(1)R colocalization, demonstrated in double immunofluorescence experiments with confocal laser microscopy, was found in both cotransfected fibroblast cells and cortical neurons in culture. On the other hand, a low degree of A(1)R and D(2)R colocalization was observed in cotransfected fibroblasts. Pretreatment with the A(1)R agonist caused coclustering (coaggregation) of A(1)R and D(1)R, which was blocked by combined pretreatment with the D(1)R and A(1)R agonists in both fibroblast cells and in cortical neurons in culture. Combined pretreatment with D(1)R and A(1)R agonists, but not with either one alone, substantially reduced the D(1)R agonist-induced accumulation of cAMP. The A(1)R/D(1)R heteromerization may be one molecular basis for the demonstrated antagonistic modulation of A(1)R of D(1)R receptor signaling in the brain. The persistence of A(1)R/D(1)R heteromerization seems to be essential for the blockade of A(1)R agonist-induced A(1)R/D(1)R coclustering and for the desensitization of the D(1)R agonist-induced cAMP accumulation seen on combined pretreatment with D(1)R and A(1)R agonists, which indicates a potential role of A(1)R/D(1)R heteromers also in desensitization mechanisms and receptor trafficking.
453 citations
"Recent developments in adenosine re..." refers background in this paper
...10 T ec ad en os on [ 10 9] 6....
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...3 C PA [ 10 9] 2....
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...37 C P5 32 ,9 03 [ 10 3] 89 8 (m ) > 1 0, 00 0 (m ) > 10 ,0 00 ( m ) 9....
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...30 C lIB -M E C A ( C F1 02 ) 22 0 (h ) [1 09 ] 53 60 ( h) [ 10 9] > 10 ,0 00 ( h) [ 13 4] 1....
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...83 ( h) [ 10 9] 22 70 ( h) [ 10 9] 18 ,8 00 ( h) [ 10 9] 38 ( h) [ 10 9]...
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