Molecular probes for the human adenosine receptors

AbstractAdenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail.

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Role and Function of Adenosine and its Receptors in Inflammation, Neuroinflammation, IBS, Autoimmune Inflammatory Disorders, Rheumatoid Arthritis and Psoriasis

Current Pharmaceutical Design ◽

10.2174/1381612825666190716145206 ◽

2019 ◽

Vol 25 (26) ◽

pp. 2875-2891 ◽

Cited By ~ 3

Author(s):

Ashok K. Shakya ◽

Rajashri R. Naik ◽

Ihab M. ALMASRI ◽

Avneet Kaur

Keyword(s):

Rheumatoid Arthritis ◽

Adenosine Receptors ◽

G Protein Coupled Receptors ◽

Physiological Effects ◽

Xanthine Derivatives ◽

Organ Systems ◽

New Chemical Entities ◽

And Function ◽

G Protein Coupled ◽

Role And Function

The physiological effects of endogenous adenosine on various organ systems are very complex and numerous which are elicited upon activation of any of the four G-protein-coupled receptors (GPCRs) denoted as A1, A2A, A2B and A3 adenosine receptors (ARs). Several fused heterocyclic and non-xanthine derivatives are reported as a possible target for these receptors due to physiological problems and lack of selectivity of xanthine derivatives. In the present review, we have discussed the development of various new chemical entities as a target for these receptors. In addition, compounds acting on adenosine receptors can be utilized in treating diseases like inflammation, neuroinflammation, autoimmune and related diseases.

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Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms20215475 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5475 ◽

Cited By ~ 6

Author(s):

Nina Wolska ◽

Marcin Rozalski

Keyword(s):

Adenosine Receptor ◽

Adenosine Receptors ◽

Purinergic Receptor ◽

Blood Platelets ◽

Blood Platelet ◽

Intracellular Camp ◽

Receptor Subtypes ◽

Adenosine Receptor Agonists ◽

Anti Platelet Therapy ◽

G Protein Coupled

Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A2A and A2B) of the four known adenosine receptor subtypes (A1, A2A, A2B, and A3). Agonization of these receptors results in an enhanced intracellular cAMP and the inhibition of platelet activation and aggregation. Therefore, adenosine receptors A2A and A2B could be targets for anti-platelet therapy, especially under circumstances when classic therapy based on antagonizing the purinergic receptor P2Y12 is insufficient or problematic. Apart from adenosine, there is a group of synthetic, selective, longer-lasting agonists of A2A and A2B receptors reported in the literature. This group includes agonists with good selectivity for A2A or A2B receptors, as well as non-selective compounds that activate more than one type of adenosine receptor. Chemically, most A2A and A2B adenosine receptor agonists are adenosine analogues, with either adenine or ribose substituted by single or multiple foreign substituents. However, a group of non-adenosine derivative agonists has also been described. This review aims to systematically describe known agonists of A2A and A2B receptors and review the available literature data on their effects on platelet function.

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Adenosine Receptors as Targets for Therapeutic Intervention

Kathmandu University Medical Journal ◽

10.3126/kumj.v11i1.11054 ◽

2014 ◽

Vol 11 (1) ◽

pp. 96-101 ◽

Cited By ~ 1

Author(s):

B Suvarna

Keyword(s):

Medical Journal ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Receptor Subtypes ◽

Therapeutic Application ◽

Chemistry Research ◽

Wide Range ◽

The World ◽

Selective Agonists ◽

Receptor Modulators

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. DOI: http://dx.doi.org/10.3126/kumj.v11i1.11054 Kathmandu University Medical Journal Vol.11(1) 2013: 96-101

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PET Imaging of Adenosine Receptors in Diseases

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190708163407 ◽

2019 ◽

Vol 19 (16) ◽

pp. 1445-1463 ◽

Cited By ~ 3

Author(s):

Jindian Li ◽

Xingfang Hong ◽

Guoquan Li ◽

Peter S. Conti ◽

Xianzhong Zhang ◽

...

Keyword(s):

Pet Imaging ◽

Adenosine Receptors ◽

Neurological Diseases ◽

G Protein Coupled Receptors ◽

Extracellular Adenosine ◽

Positron Emission ◽

Imaging Probes ◽

Pet Probes ◽

Cancer And Inflammation ◽

G Protein Coupled

Adenosine receptors (ARs) are a class of purinergic G-protein-coupled receptors (GPCRs). Extracellular adenosine is a pivotal regulation molecule that adjusts physiological function through the interaction with four ARs: A1R, A2AR, A2BR, and A3R. Alterations of ARs function and expression have been studied in neurological diseases (epilepsy, Alzheimer’s disease, and Parkinson’s disease), cardiovascular diseases, cancer, and inflammation and autoimmune diseases. A series of Positron Emission Tomography (PET) probes for imaging ARs have been developed. The PET imaging probes have provided valuable information for diagnosis and therapy of diseases related to alterations of ARs expression. This review presents a concise overview of various ARs-targeted radioligands for PET imaging in diseases. The most recent advances in PET imaging studies by using ARs-targeted probes are briefly summarized.

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Mapping the Heart

Microscopy Today ◽

10.1017/s155192951000043x ◽

2010 ◽

Vol 18 (4) ◽

pp. 6-8

Author(s):

Stephen W. Carmichael

Keyword(s):

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

G Protein Coupled Receptors ◽

Receptor Subtypes ◽

Cardiac Muscle Cells ◽

Guanine Nucleotide Binding Protein ◽

The Common ◽

Guanine Nucleotide Binding ◽

First Time ◽

G Protein Coupled

Some of the receptors on the surface of cardiac muscle cells (cardiomyocytes) mediate the response of these cells to catecholamines by causing the production of the common second messenger cyclic adenosine monophosphate (cAMP). An example of such receptors are the β1- and β2-adrenergic receptors (βARs) that are heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Selective stimulation of these two receptor subtypes leads to distinct physiological and pathophysiological responses, but their precise location on the surface of cardiomyocytes has not been correlated with these responses. In an ingenious combination of techniques, Viacheslav Nikolaev, Alexey Moshkov, Alexander Lyon, Michele Miragoli, Pavel Novak, Helen Paur, Martin Lohse, Yuri Korchev, Sian Harding, and Julia Gorelik have mapped the function of these receptors for the first time.

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GRKs as Modulators of Neurotransmitter Receptors

Cells ◽

10.3390/cells10010052 ◽

2020 ◽

Vol 10 (1) ◽

pp. 52

Author(s):

Eugenia V. Gurevich ◽

Vsevolod V. Gurevich

Keyword(s):

G Protein ◽

General Model ◽

G Protein Coupled Receptors ◽

Receptor Internalization ◽

Neurotransmitter Receptors ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Receptor Kinase ◽

G Protein Coupled ◽

Homologous Desensitization

Many receptors for neurotransmitters, such as dopamine, norepinephrine, acetylcholine, and neuropeptides, belong to the superfamily of G protein-coupled receptors (GPCRs). A general model posits that GPCRs undergo two-step homologous desensitization: the active receptor is phosphorylated by kinases of the G protein-coupled receptor kinase (GRK) family, whereupon arrestin proteins specifically bind active phosphorylated receptors, shutting down G protein-mediated signaling, facilitating receptor internalization, and initiating distinct signaling pathways via arrestin-based scaffolding. Here, we review the mechanisms of GRK-dependent regulation of neurotransmitter receptors, focusing on the diverse modes of GRK-mediated phosphorylation of receptor subtypes. The immediate signaling consequences of GRK-mediated receptor phosphorylation, such as arrestin recruitment, desensitization, and internalization/resensitization, are equally diverse, depending not only on the receptor subtype but also on phosphorylation by GRKs of select receptor residues. We discuss the signaling outcome as well as the biological and behavioral consequences of the GRK-dependent phosphorylation of neurotransmitter receptors where known.

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Adhesion GPCRs in Glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab046 ◽

2021 ◽

Author(s):

Gabriele Stephan ◽

Niklas Ravn-Boess ◽

Dimitris G Placantonakis

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

The Past ◽

Novel Treatment ◽

The Family ◽

Health And Disease ◽

Basic Biology ◽

G Protein Coupled ◽

Potential Use ◽

Receptor Family

Abstract Members of the adhesion family of G protein-coupled receptors (GPCRs) have received attention for their roles in health and disease, including cancer. Over the past decade, several members of the family have been implicated in the pathogenesis of glioblastoma. Here, we discuss the basic biology of adhesion GPCRs and review in detail specific members of the receptor family with known functions in glioblastoma. Finally, we discuss the potential use of adhesion GPCRs as novel treatment targets in neuro-oncology.

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