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Adenosine A2B receptor

Shirin Kashfi, Kamran Ghaedi, Hossein Baharvand, Mohammad Hossein Nasr-Esfahani, Mohammad Javan
Adenosine is an endogenous, autacoid purine nucleoside which performs many important biological roles, particularly during stressful events. Adenosine can signal through four adenosine receptor (AR) subtypes: A1, A2A, A2B, and A3. Of these, adenosine A1 receptor (A1AR) has a broad, wide distribution throughout different vertebrate cell types and the highest affinity to adenosine. The A1AR-dependent action of adenosine is well documented in reports from numerous studies that have used different selective A1AR agonists and antagonists as well as in animals that have a genetically manipulated A1AR gene...
November 26, 2016: Molecular Neurobiology
Raquel Guinzberg, Antonio Díaz-Cruz, Carlos Acosta-Trujillo, María Magdalena Vilchis-Landeros, Héctor Vázquez-Meza, Carlos Lozano-Flores, Natalia Chiquete-Felix, Alfredo Varela-Echavarría, Salvador Uribe-Carvajal, Héctor Riveros-Rosas, Enrique Piña
Spatiotemporal regulation of cAMP within the cell is required to achieve receptor-specific responses. The mechanism through which the cell selects a specific response to new synthesized cAMP is not fully understood. In hepatocyte plasma membranes, we identified two functional and independent cAMP-responsive signaling protein macrocomplexes that produce, use, degrade, and regulate their own non-diffusible (sequestered) cAMP pool to achieve their specific responses. Each complex responds to the stimulation of an adenosine G-protein coupled receptor (Ado-GPCR), bound to either A2A or A2B , but not simultaneously to both...
November 19, 2016: FEBS Journal
Sujay Basu, Dinesh A Barawkar, Vidya Ramdas, Yogesh Waman, Meena Patel, Anil Panmand, Santosh Kumar, Sachin Thorat, Rajesh Bonagiri, Dilip Jadhav, Partha Mukhopadhyay, Vandna Prasad, B Srinivasa Reddy, Arnab Goswami, Sandhya Chaturvedi, Suraj Menon, Azfar Quraishi, Indraneel Ghosh, Sushant Dusange, Shalini Paliwal, Abhay Kulkarni, Vikas Karande, Rhishikesh Thakre, Gaurav Bedse, Sreekanth Rouduri, Jayasagar Gundu, Venkata P Palle, Anita Chugh, Kasim A Mookhtiar
A2BAdoR is a low affinity adenosine receptor that functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like COPD and asthma. Several potent and selective A2BAdoR antagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile. Therefore, with the aim to identify novel, potent and selective A2BAdoR antagonists with improved pharmacokinetic properties, we first explored more constrained form of MRS-1754 (4)...
November 8, 2016: European Journal of Medicinal Chemistry
Song-Bing He, Ben Hu, Zheng-Kun Kuang, Dong Wang, De-Xin Kong
Adenosine receptors (ARs) are potential therapeutic targets for Parkinson's disease, diabetes, pain, stroke and cancers. Prediction of subtype selectivity is therefore important from both therapeutic and mechanistic perspectives. In this paper, we introduced a shape similarity profile as molecular descriptor, namely three-dimensional biologically relevant spectrum (BRS-3D), for AR selectivity prediction. Pairwise regression and discrimination models were built with the support vector machine methods. The average determination coefficient (r(2)) of the regression models was 0...
November 4, 2016: Scientific Reports
Jesus Mendiola-Precoma, Karla Padilla, Alfredo Rodríguez-Cruz, Laura C Berumen, Ricardo Miledi, Guadalupe García-Alcocer
Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled...
October 24, 2016: Journal of Alzheimer's Disease: JAD
Wilfried Dinh, Barbara Albrecht-Küpper, Mihai Gheorghiade, Adriaan A Voors, Michael van der Laan, Hani N Sabbah
Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels...
October 22, 2016: Handbook of Experimental Pharmacology
Hendrik Busse, Diane Bitzinger, Klaus Höcherl, Timo Seyfried, Michael Gruber, Bernhard M Graf, York A Zausig
INTRODUCTION: Mechanical and morphological ischemia and reperfusion (I/R) injury is reduced in septic hearts. The mechanism behind this "cardioprotection" is less well understood. As adenosine receptors play a major role for cardioprotection in non-septic hearts, we investigated the influence of adenosine receptors in a model of I/R in septic hearts. METHODS: SHAM operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats (n = 60)...
October 18, 2016: Cardiovascular Drugs and Therapy
Cesar Sepúlveda, Iván Palomo, Eduardo Fuentes
The adenosine A2b receptor is a G-protein coupled receptor. Its activation occurs with high extracellular adenosine concentration, for example in inflammation or hypoxia. These conditions are generated in the tumor environment. Studies show that A2b receptor is overexpressed in various tumor lines and biopsies from patients with different cancers. This suggests that A2b receptor can be used by tumor cells to promote progression. Thus A2b participates in different events, such as angiogenesis and metastasis, besides exerting immunomodulatory effects that protect tumor cells...
October 8, 2016: Life Sciences
Christina Mølck, James Ryall, Laura M Failla, Janine L Coates, Jean-Marc Pascussi, Joan K Heath, Gregory Stewart, Frédéric Hollande
PURPOSE: Adenosine is a multifaceted regulator of tumor progression. It modulates immune cell activity as well as acting directly on tumor cells. The A2b adenosine receptor (A2b-AR) is thought to be an important mediator of these effects. In this study we sought to analyze the contribution of the A2b-AR to the behavior of colorectal cancer cells. PRINCIPAL RESULTS: The A2b-AR antagonist PSB-603 changed cellular redox state without affecting cellular viability. Quantification of cellular bioenergetics demonstrated that PSB-603 increased basal oxygen consumption rates, indicative of enhanced mitochondrial oxidative phosphorylation...
September 28, 2016: Cancer Letters
Matthias Klein, Tobias Bopp
T regulatory (Treg) cells are one of the key players in the immune tolerance network, and a plethora of manuscripts have described their development and function in the course of the last two decades. Nevertheless, it is still a matter of debate as to which mechanisms and agents are employed by Treg cells, providing the basis of their suppressive potency. One of the important candidates is cyclic AMP (cAMP), which is long known as a potent suppressor at least of T cell activation and function. While this suppressive function by itself is widely accepted, the source and the mechanism of action of cAMP are less clear, and a multitude of seemingly contradictory data allow for, in principle, two different scenarios of cAMP-mediated suppression...
2016: Frontiers in Immunology
Ying Sun, Pingbo Huang
Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR's functions, including certain seemingly paradoxical functions of the receptor...
2016: Frontiers in Chemistry
Claudia Sorrentino, Lucio Miele, Amalia Porta, Aldo Pinto, Silvana Morello
The A2B receptor (A2BR) can mediate adenosine-induced tumor proliferation, immunosuppression and angiogenesis. Targeting the A2BR has proved to be therapeutically effective in some murine tumor models, but the mechanisms of these effects are still incompletely understood. Here, we report that pharmacologic inhibition of A2BR with PSB1115, which inhibits tumor growth, decreased the number of fibroblast activation protein (FAP)-expressing cells in tumors in a mouse model of melanoma. This effect was associated with reduced expression of fibroblast growth factor (FGF)-2...
August 31, 2016: Oncotarget
Alessandra Bortoluzzi, Fabrizio Vincenzi, Marcello Govoni, Melissa Padovan, Annalisa Ravani, Pier Andrea Borea, Katia Varani
BACKGROUND: Adenosine is a purine nucleoside implicated in the regulation of the innate and adaptive immune systems, acting through its interaction with four cell surface receptors: A1, A2A, A2B, and A3. There is intense interest in understanding how adenosine functions in health and during disease, but surprisingly little is known about the actual role of adenosine-mediated mechanisms in systemic lupus erythematosus (SLE). With this background, the aim of the present study was to test the hypothesis that dysregulation of A1, A2A, A2B, and A3 adenosine receptors (ARs) in lymphocytes of patients with SLE may be involved in the pathogenesis of the disease and to examine the correlations between the status of the ARs and the clinical parameters of SLE...
2016: Arthritis Research & Therapy
Joachim C Burbiel, Wadih Ghattas, Petra Küppers, Meryem Köse, Svenja Lacher, Anna-Maria Herzner, Rajan Subramanian Kombu, Raghuram Rao Akkinepally, Jörg Hockemeyer, Christa E Müller
2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A3 AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, Ki human A3 AR 1.16 nm) and 5'-phenyl-1,2-dihydro-3'H-spiro[indole-3,2'-[1,2,4]triazolo[1,5-c]quinazolin]-2-one (20, Ki human A3 AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A1 /A3 antagonist 2,5-diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13 b, Ki human A1 AR 51...
August 17, 2016: ChemMedChem
Elizabeth A Vecchio, Chung Hui Chuo, Jo-Anne Baltos, Leigh Ford, Peter J Scammells, Bing H Wang, Arthur Christopoulos, Paul J White, Lauren T May
We have recently described the rationally-designed adenosine receptor agonist, 4-(5-amino-4-benzoyl-3-(3-(trifluoromethyl)phenyl)thiophen-2-yl)-N-(6-(9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxylmethyl)tetrahydro-furan-2-yl)-9H-purin-6-ylamino)hexyl)benzamide (VCP746), a hybrid molecule consisting of an adenosine moiety linked to an adenosine A1 receptor (A1AR) allosteric modulator moiety. At the A1AR, VCP746 mediated cardioprotection in the absence of haemodynamic side effects such as bradycardia. The current study has now identified VCP746 as an important pharmacological tool for the adenosine A2B receptor (A2BAR)...
October 1, 2016: Biochemical Pharmacology
Rosa M Andrés, M Carmen Terencio, Jorge Arasa, Miguel Payá, Francisca Valcuende-Cavero, Pedro Navalón, M Carmen Montesinos
Adenosine is a potent regulator of inflammation and immunity, but the role of adenosine receptors in keratinocytes remains controversial. We determined that in addition to A2B receptors, human epidermal keratinocytes also express A2A receptors, although to a lower extent. Through the use of selective adenosine receptor agonists and antagonists we demonstrated that physiological concentrations of adenosine activate A2B receptors in normal human keratinocytes, inducing cell cycle arrest through the increase of intracellular calcium but not through cAMP signaling...
August 3, 2016: Journal of Investigative Dermatology
Patrick F Wilkinson, Francis X Farrell, Diane Morel, William Law, Suzanne Murphy
Interstitial renal fibrosis is a major pathophysiological manifestation of patients diagnosed with Chronic Kidney Disease (CKD), Diabetic Nephropathy (DN) and other inflammatory diseases. Adenosine signaling is an innate autocrine and paracrine cellular signaling pathway involving several key mediators that are elevated in the blood and kidneys of patients with DN. In these studies, we hypothesized that extracellular adenosine signals through one or more functional adenosine GPCRs on renal fibroblasts which increases profibrotic and proinflammatory mediators by inducing an activated fibroblast phenotype...
July 2016: Annals of Clinical and Laboratory Science
Ranju Bansal, Gulshan Kumar, Suman Rohilla, Karl-Norbert Klotz, Sonja Kachler, Louise C Young, Alan L Harvey
Preclinical Research A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds...
August 2016: Drug Development Research
Xia Hu, Morayo G Adebiyi, Jialie Luo, Kaiqi Sun, Thanh-Thuy T Le, Yujin Zhang, Hongyu Wu, Shushan Zhao, Harry Karmouty-Quintana, Hong Liu, Aji Huang, Yuan Edward Wen, Oleg L Zaika, Mykola Mamenko, Oleh M Pochynyuk, Rodney E Kellems, Holger K Eltzschig, Michael R Blackburn, Edgar T Walters, Dong Huang, Hongzhen Hu, Yang Xia
The molecular mechanisms of chronic pain are poorly understood and effective mechanism-based treatments are lacking. Here, we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected chronic mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine. Extending from Ada(-/-) mice, we further discovered that prolonged elevated adenosine contributed to chronic pain behaviors in two additional independent animal models: sickle cell disease mice, a model of severe pain with limited treatment, and complete Freund's adjuvant paw-injected mice, a well-accepted inflammatory model of chronic pain...
June 28, 2016: Cell Reports
Bunyen Teng, Stephen L Tilley, Catherine Ledent, S Jamal Mustafa
Bolus injections of adenosine and the A2A adenosine receptor (AR) selective agonist (regadenoson) are used clinically as a substitute for a stress test in people who cannot exercise. Using isolated tissue preparations, our lab has shown that coronary flow and cardiac effects of adenosine are mostly regulated by the AR subtypes A1, A2A, and A2B In this study, we used ultrasound imaging to measure the in vivo effects of adenosine on coronary blood flow (left coronary artery) and cardiac function in anesthetized wild-type, A1 knockout (KO), A2AKO, A2BKO, A3KO, A1, and A3 double KO (A1/3 DKO) and A2A and A2B double KO (A2A/2B DKO) mice in real time...
June 2016: Physiological Reports
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