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adenosine a2a receptor

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
Dmitry Mayorov, Sergey Kasparov, Julian Paton
OBJECTIVE: Functional defects in purinergic neurotransmission, and specifically adenosine A1 receptor, have been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Here, we examined the role of adenosine receptors in regulating cerebrovascular function in pre-hypertensive SHR. DESIGN AND METHOD: Changes in the diameter of pial arterioles (20-100 μm) in response to adenosine A1 and A2 receptor agonists were assessed after pre-constriction with the thromboxane agonist U46619 in slices from the brainstem and cortex of 4-6 week-old Wistar and SHR...
September 2016: Journal of Hypertension
L Caetano, H Pinheiro, P Patrício, A Mateus-Pinheiro, N D Alves, B Coimbra, F I Baptista, S N Henriques, C Cunha, A R Santos, S G Ferreira, V M Sardinha, J F Oliveira, A F Ambrósio, N Sousa, R A Cunha, A J Rodrigues, L Pinto, C A Gomes
Developmental risk factors, such as the exposure to stress or high levels of glucocorticoids (GCs), may contribute to the pathogenesis of anxiety disorders. The immunomodulatory role of GCs and the immunological fingerprint found in animals prenatally exposed to GCs point towards an interplay between the immune and the nervous systems in the etiology of these disorders. Microglia are immune cells of the brain, responsive to GCs and morphologically altered in stress-related disorders. These cells are regulated by adenosine A2A receptors, which are also involved in the pathophysiology of anxiety...
October 11, 2016: Molecular Psychiatry
M M van der Walt, G Terre'Blanche
Recent research exploring C8 substitution on the caffeine core identified 8-(2-phenylethyl)-1,3,7-trimethylxanthine as a non-selective adenosine receptor antagonist. To elaborate further, we included various C8 two-chain-length linkers to enhance adenosine receptor affinity. The results indicated that the unsubstituted benzyloxy linker (1e A1Ki = 1.52 μM) displayed the highest affinity for the A1 adenosine receptor and the para-chloro-substituted phenoxymethyl (1d A2AKi = 1.33 μM) linker the best A2A adenosine receptor affinity...
September 23, 2016: European Journal of Medicinal Chemistry
Daniela Poli, Matteo Falsini, Flavia Varano, Marco Betti, Katia Varani, Fabrizio Vincenzi, Anna Maria Pugliese, Felicita Pedata, Diego Dal Ben, Ajiroghene Thomas, Ilaria Palchetti, Francesca Bettazzi, Daniela Catarzi, Vittoria Colotta
The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A3 or the hA2A receptor subtype. The N(8)-(hetero)arylcarboxyamido substituted compounds 4-14 and 21-30, bearing a 6-phenyl moiety or not, respectively, show good hA3 receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA2A receptor subtype (compounds 31-38) and also the 6-phenyl analogues 18-20 do not bind the hA2A AR, or show hA1 or balanced hA1/hA2A AR affinity in the micromolar range...
September 26, 2016: European Journal of Medicinal Chemistry
Georgios Alachouzos, Eelke B Lenselink, Thea Mulder-Krieger, Henk de Vries, Adriaan P IJzerman, Julien Louvel
We report the synthesis and biological evaluation of new 2-amino-4,5-diarylpyrimidines as selective antagonists at the adenosine A1 receptor. The scaffold they are based upon is a deaza variation of a previously reported collection of 3-amino-5,6-diaryl-1,2,4-triazines, members of which had a subnanomolar affinity but limited selectivity over the A2A subtype. Initially, similar structure-affinity relationships at the 5-aryl ring were established, and then emphasis was put on increasing selectivity at the hA1AR by introducing substituents on the N(2)-position, all the while maintaining a nanomolar affinity...
September 26, 2016: European Journal of Medicinal Chemistry
Supriyo Bhattacharya, Romelia Salomon-Ferrer, Sangbae Lee, Nagarajan Vaidehi
GPCRs are transmembrane receptors involved in diverse biological functions. Despite the diversity in their amino acid sequences, class A GPCRs exhibit a conserved structural topology and possibly common mechanism of receptor activation. To understand how this high sequence diversity translates to a conserved functional mechanism, we have compared the dynamic behavior of eight class A GPCRs comprising of six biogenic amine receptors, and the adenosine A2A and a peptide receptor protease activated receptor 1...
October 6, 2016: Journal of Chemical Theory and Computation
Jesenia Acurio, Kurt Herlitz, Felipe Troncoso, Claudio Aguayo, Patricio Bertoglia, Carlos Escudero
We aim to investigate whether A2A/nitric oxide-mediated regulation of vascular endothelial growth factor (VEGF) expression is impaired in feto-placental endothelial cells from late-onset pre-eclampsia. Cultures of human umbilical vein endothelial cells (HUVECs) and human placental microvascular endothelial cells (hPMECs) from normal and pre-eclamptic pregnancies were used. Assays by using small interference RNA (siRNA) for A2A were performed, and transfected cells were used for estimation of messenger RNA (mRNA) levels of VEGF, as well as for cell proliferation and angiogenesis in vitro...
September 30, 2016: Purinergic Signalling
Riyaad Aungraheeta, Alexandra Conibear, Mark Butler, Eamonn Kelly, Sven Nylander, Andrew Mumford, Stuart Mundell
Ticagrelor is a potent antagonist of the P2Y12 receptor (P2Y12R) and consequently an inhibitor of platelet activity effective in the treatment of atherothrombosis. Here, we sought to further characterise its molecular mechanism of action. Initial studies showed that ticagrelor promoted a greater inhibition of ADP-induced Ca(2+) release in washed platelets versus other P2Y12R antagonists. This additional effect of ticagrelor beyond P2Y12R antagonism was in part as a consequence of ticagrelor inhibiting the equilibrative nucleoside transporter 1 (ENT1) on platelets, leading to accumulation of extracellular adenosine and activation of Gs-coupled adenosine A2A receptors...
September 30, 2016: Blood
Anna Dziubina, Karina Szmyd, Małgorzata Zygmunt, Jacek Sapa, Magdalena Dudek, Barbara Filipek, Anna Drabczyńska, Michał Załuski, Karolina Pytka, Katarzyna Kieć-Kononowicz
BACKGROUND: It has recently been suggested that the adenosine A2A receptor plays a role in several animal models of depression. Additionally, A2A antagonists have reversed behavioral deficits and exhibited a profile similar to classical antidepressants. METHODS: In the present study, imidazo- and pyrimido[2,1-f]purinedione derivatives (KD 66, KD 167, KD 206) with affinity to A2A receptors but poor A1 affinity were evaluated for their antidepressant- and anxiolytic-like activity...
July 25, 2016: Pharmacological Reports: PR
Alexander Batyuk, Lorenzo Galli, Andrii Ishchenko, Gye Won Han, Cornelius Gati, Petr A Popov, Ming-Yue Lee, Benjamin Stauch, Thomas A White, Anton Barty, Andrew Aquila, Mark S Hunter, Mengning Liang, Sébastien Boutet, Mengchen Pu, Zhi-Jie Liu, Garrett Nelson, Daniel James, Chufeng Li, Yun Zhao, John C H Spence, Wei Liu, Petra Fromme, Vsevolod Katritch, Uwe Weierstall, Raymond C Stevens, Vadim Cherezov
Serial femtosecond crystallography (SFX) takes advantage of extremely bright and ultrashort pulses produced by x-ray free-electron lasers (XFELs), allowing for the collection of high-resolution diffraction intensities from micrometer-sized crystals at room temperature with minimal radiation damage, using the principle of "diffraction-before-destruction." However, de novo structure factor phase determination using XFELs has been difficult so far. We demonstrate the ability to solve the crystallographic phase problem for SFX data collected with an XFEL using the anomalous signal from native sulfur atoms, leading to a bias-free room temperature structure of the human A2A adenosine receptor at 1...
September 2016: Science Advances
Adriana Pinto de Freitas, Danielle Dias Pinto Ferreira, Arlete Fernandes, Robertta Silva Martins, Vladimir Pedro Peralva Borges-Martins, Matheus Figueiredo Sathler, Maurício Dos-Santos-Pereira, Roberto Paes-de-Carvalho, Elizabeth Giestal-de-Araujo, Ricardo Augusto de Melo Reis, Regina Celia Cussa Kubrusly
l-Glutamate and l-aspartate are the main excitatory amino acids (EAAs) in the Central Nervous System (CNS) and their uptake regulation is critical for the maintenance of the excitatory balance. Excitatory amino acid transporters (EAATs) are widely distributed among central neurons and glial cells. GLAST and GLT1 are expressed in glial cells, whereas excitatory amino acid transporter 3/excitatory amino acid carrier 1 (EAAT3/EAAC1) is neuronal. Different signaling pathways regulate glutamate uptake by modifying the activity and expression of EAATs...
September 20, 2016: Neuroscience
Andreas Brunschweiger, Pierre Koch, Miriam Schlenk, Muhammad Rafehi, Hamid Radjainia, Petra Küppers, Sonja Hinz, Felipe Pineda, Michael Wiese, Jörg Hockemeyer, Jag Heer, Frédéric Denonne, Christa E Müller
Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs...
November 1, 2016: Bioorganic & Medicinal Chemistry
Xiaoying Huang, Yicheng He, Yanfan Chen, Peiliang Wu, Di Gui, Hui Cai, Ali Chen, Mayun Chen, Caijun Dai, Dan Yao, Liangxing Wang
BACKGROUND: Baicalin has been reported to have anti-fibrosis effect; however, its mechanism still remains to be elucidated. Adenosine A2a receptor (A2aR) is a novel inflammation regulator, and transforming growth factor-β1 (TGF-β1)-induced extracellular signal regulated kinase1/2 (ERK1/2) signaling pathway plays an important role in idiopathic pulmonary fibrosis (IPF). This study was to explore the relationship of A2aR and TGF-β1-induced ERK1/2 in bleomycin (BLM)-induced pulmonary fibrosis in mice, and to investigate whether A2aR mediate the anti-fibrosis effect of Baicalin on BLM-induced pulmonary fibrosis...
2016: BMC Pulmonary Medicine
Aurora R Barros-Barbosa, Fátima Ferreirinha, Ângela Oliveira, Marina Mendes, M Graça Lobo, Agostinho Santos, Rui Rangel, Julie Pelletier, Jean Sévigny, J Miguel Cordeiro, Paulo Correia-de-Sá
Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A1 receptors. Gain of function of the excitatory A2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity...
September 20, 2016: Purinergic Signalling
Dmitry Mayorov, Sergey Kasparov, Julian Paton
OBJECTIVE: Functional defects in purinergic neurotransmission, and specifically adenosine A1 receptor, have been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Here, we examined the role of adenosine receptors in regulating cerebrovascular function in pre-hypertensive SHR. DESIGN AND METHOD: Changes in the diameter of pial arterioles (20-100 μm) in response to adenosine A1 and A2 receptor agonists were assessed after pre-constriction with the thromboxane agonist U46619 in slices from the brainstem and cortex of 4-6 week-old Wistar and SHR...
September 2016: Journal of Hypertension
Byron Carpenter, Rony Nehmé, Tony Warne, Andrew G W Leslie, Christopher G Tate
No abstract text is available yet for this article.
September 14, 2016: Nature
Eelke B Lenselink, Thijs Beuming, Corine van Veen, Arnault Massink, Woody Sherman, Herman W T van Vlijmen, Adriaan P IJzerman
In this work, we present a case study to explore the challenges associated with finding novel molecules for a receptor that has been studied in depth and has a wealth of chemical information available. Specifically, we apply a previously described protocol that incorporates explicit water molecules in the ligand binding site to prospectively screen over 2.5 million drug-like and lead-like compounds from the commercially available eMolecules database in search of novel binders to the adenosine A2A receptor (A2AAR)...
September 15, 2016: Journal of Computer-aided Molecular Design
Arabella Young, Shin Foong Ngiow, Deborah S Barkauskas, Erin Sult, Carl Hay, Stephen J Blake, Qihui Huang, Jing Liu, Kazuyoshi Takeda, Michele W L Teng, Kris Sachsenmeier, Mark J Smyth
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors...
September 12, 2016: Cancer Cell
Sènan M d'Almeida, Gilles Kauffenstein, Charlotte Roy, Laetitia Basset, Loukas Papargyris, Daniel Henrion, Véronique Catros, Norbert Ifrah, Philippe Descamps, Anne Croue, Pascale Jeannin, Marc Grégoire, Yves Delneste, Julie Tabiasco
Tumor-associated macrophages (TAM) are immunosuppressive cells that can massively accumulate in the tumor microenvironment. In patients with ovarian cancer, their density is correlated with poor prognosis. Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor...
July 2016: Oncoimmunology
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