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adenosine a2a receptor

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https://www.readbyqxmd.com/read/29338068/single-and-combined-effects-of-plant-derived-thc-cbd-and-synthetic-win-55-212-cannabinoids-on-cognition-and-cannabinoid-associated-withdrawal-signs-in-mice
#1
Alyssa M Myers, Patrick B Siegele, Jeffrey D Foss, Ronald F Tuma, Sara Jane Ward
BACKGROUND AND PURPOSE: It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of delta-9-tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1/CB2 receptor agonists or produces these pharmacological effects on its own. EXPERIMENTAL APPROACH: The effects of THC or the CB1/CB2 receptor full agonist WIN55212 (WIN) alone, CBD alone, or their combination were tested across a range of doses...
January 16, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29334795/progress-in-the-development-of-histamine-h3-receptor-antagonists-inverse-agonists-a-patent-review-2013-2017
#2
Dorota Łażewska, Katarzyna Kieć-Kononowicz
Since years, ligands blocking histamine H3 receptor (H3R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H3R antagonists/inverse agonists. Some of them have reached to clinical trials. Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H3R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials...
January 15, 2018: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29332604/the-effect-of-an-adenosine-a2a-agonist-on-intra-tumoral-concentrations-of-temozolomide-in-patients-with-recurrent-glioblastoma
#3
Sadhana Jackson, Jon Weingart, Edjah K Nduom, Thura T Harfi, Richard T George, Dorothea McAreavey, Xiaobu Ye, Nicole M Anders, Cody Peer, William D Figg, Mark Gilbert, Michelle A Rudek, Stuart A Grossman
BACKGROUND: The blood-brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A2A receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A2A receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma. METHODS: Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible...
January 15, 2018: Fluids and Barriers of the CNS
https://www.readbyqxmd.com/read/29329032/targeting-expression-of-adenosine-receptors-during-hypoxia-induced-angiogenesis-a-study-using-zebrafish-model
#4
Navina Panneerselvan, Malathi Ragunathan
Hypoxia is known to be a major player during pathological angiogenesis and adenosine as a negative feedback signaling to maintain oxygen delivery in pathological ischemic condition. We mimicked hypoxic condition and studied angiogenesis by inducing adenosine receptors using forskolin, a plant compound and NECA analogue of adenosine using zebrafish model. Vascular endothelial growth factor (VEGF) is known to play a key role during pathological angiogenesis and regulated by the factors HIF1a under hypoxic condition and recently Notch is proposed to play a negative feedback loop mechanism along with VEGF signaling but the role of adenosine receptor during the process is not known...
January 9, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29315766/disruption-of-adenosine-2a-receptor-exacerbates-nafld-through-increasing-inflammatory-responses-and-srebp1c-activity
#5
Yuli Cai, Honggui Li, Mengyang Liu, Ya Pei, Juan Zheng, Jing Zhou, Xianjun Luo, Wenya Huang, Linqiang Ma, Qiuhua Yang, Shaodong Guo, Xiaoqiu Xiao, Qifu Li, Tianshu Zeng, Fanyin Meng, Heather Francis, Shannon Glaser, Lulu Chen, Yuqing Huo, Gianfranco Alpini, Chaodong Wu
Adenosine 2A receptor (A2A R) exerts protective roles in endotoxin- and/or ischemia-induced tissue damages. However, the role for A2A R in non-alcoholic fatty liver disease (NAFLD) remains largely unknown. We sought to examine the effects of global and/or myeloid cell-specific A2A R disruption on the aspects of obesity-associated NAFLD and to elucidate the underlying mechanisms. Global and/or myeloid cell-specific A2A R-disrupted mice, as well as control mice were fed a high-fat diet (HFD) to induce NAFLD. Also, bone marrow-derived macrophages and primary mouse hepatocytes were examined for inflammatory and metabolic responses...
January 9, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29315226/unfolding-role-of-a-danger-molecule-adenosine-signaling-in-modulation-of-microbial-infection-and-host-cell-response
#6
REVIEW
Jaden S Lee, Özlem Yilmaz
Ectonucleotidases CD39 and CD73, specific nucleotide metabolizing enzymes located on the surface of the host, can convert a pro-inflammatory environment driven by a danger molecule extracellular-ATP to an adenosine-mediated anti-inflammatory milieu. Accordingly, CD39/CD73 signaling have has strongly implicated in modulating the intensity, duration, and composition of purinergic danger signals delivered to host. Recent studies have eluted potential roles for CD39 and CD73 in selective triggering of a variety of host immune cells and molecules in the presence of pathogenic microorganisms or microbial virulence molecules...
January 9, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29311713/towards-high-throughput-gpcr-crystallography-in-meso-soaking-of-adenosine-a2a-receptor-crystals
#7
Prakash Rucktooa, Robert K Y Cheng, Elena Segala, Tian Geng, James C Errey, Giles A Brown, Robert M Cooke, Fiona H Marshall, Andrew S Doré
Here we report an efficient method to generate multiple co-structures of the A2A G protein-coupled receptor (GPCR) with small-molecules from a single preparation of a thermostabilised receptor crystallised in Lipidic Cubic Phase (LCP). Receptor crystallisation is achieved following purification using a low affinity "carrier" ligand (theophylline) and crystals are then soaked in solutions containing the desired (higher affinity) compounds. Complete datasets to high resolution can then be collected from single crystals and seven structures are reported here of which three are novel...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29304113/discovery-of-indolylpiperazinylpyrimidines-with-dual-target-profiles-at-adenosine-a2a-and-dopamine-d2-receptors-for-parkinson-s-disease-treatment
#8
Yi-Ming Shao, Xiaohua Ma, Priyankar Paira, Aaron Tan, Deron Raymond Herr, Kah Leong Lim, Chee Hoe Ng, Gopalakrishnan Venkatesan, Karl-Norbert Klotz, Stephanie Federico, Giampiero Spalluto, Siew Lee Cheong, Yu Zong Chen, Giorgia Pastorin
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects...
2018: PloS One
https://www.readbyqxmd.com/read/29298990/gsk3%C3%AE-negatively-regulates-trax-a-scaffold-protein-implicated-in-mental-disorders-for-nhej-mediated-dna-repair-in-neurons
#9
Ting Chien, Yu-Ting Weng, Shu-Yung Chang, Hsing-Lin Lai, Feng-Lan Chiu, Hung-Chih Kuo, De-Maw Chuang, Yijuang Chern
Translin-associated protein X (TRAX) is a scaffold protein with various functions and has been associated with mental illnesses, including schizophrenia. We have previously demonstrated that TRAX interacts with a Gsα protein-coupled receptor, the A2A adenosine receptor (A2AR), and mediates the function of this receptor in neuritogenesis. In addition, stimulation of the A2AR markedly ameliorates DNA damage evoked by elevated oxidative stress in neurons derived from induced pluripotent stem cells (iPSCs). Here, we report that glycogen synthase kinase 3 beta (GSK3β) and disrupted-in-schizophrenia 1 (DISC1) are two novel interacting proteins of TRAX...
January 3, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29296811/randomized-phase-2-trial-of-regadenoson-for-treatment-of-acute-vaso-occlusive-crises-in-sickle-cell-disease
#10
Joshua J Field, Elaine Majerus, Victor R Gordeuk, Michel Gowhari, Carolyn Hoppe, Matthew M Heeney, Maureen Achebe, Alex George, Hillary Chu, Brian Sheehan, Maneka Puligandla, Donna Neuberg, Gene Lin, Joel Linden, David G Nathan
Adenosine A2A receptor (A2AR) agonists have been shown to decrease tissue inflammation induced by hypoxia/reoxygenation in mice with sickle cell disease (SCD). The key mediator of the A2AR agonist's anti-inflammatory effects is a minor lymphocyte subset, invariant natural killer T (iNKT) cells. We tested the hypothesis that administration of an A2AR agonist in patients with SCD would decrease iNKT cell activation and dampen the severity of vaso-occlusive (VO) crises. In a phase 2, randomized, placebo-controlled trial, we administered a 48-hour infusion of the A2AR agonist regadenoson (1...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290469/allosteric-coupling-of-drug-binding-and-intracellular-signaling-in-the-a2a-adenosine-receptor
#11
Matthew T Eddy, Ming-Yue Lee, Zhan-Guo Gao, Kate L White, Tatiana Didenko, Reto Horst, Martin Audet, Pawel Stanczak, Kyle M McClary, Gye Won Han, Kenneth A Jacobson, Raymond C Stevens, Kurt Wüthrich
Signaling across cellular membranes, the 826 human G protein-coupled receptors (GPCRs) govern a wide range of vital physiological processes, making GPCRs prominent drug targets. X-ray crystallography provided GPCR molecular architectures, which also revealed the need for additional structural dynamics data to support drug development. Here, nuclear magnetic resonance (NMR) spectroscopy with the wild-type-like A2A adenosine receptor (A2AAR) in solution provides a comprehensive characterization of signaling-related structural dynamics...
December 27, 2017: Cell
https://www.readbyqxmd.com/read/29290010/computer-aided-design-of-multi-target-ligands-at-a1r-a2ar-and-pde10a-key-proteins-in-neurodegenerative-diseases
#12
Leen Kalash, Cristina Val, Jhonny Azuaje, María I Loza, Fredrik Svensson, Azedine Zoufir, Lewis Mervin, Graham Ladds, José Brea, Robert Glen, Eddy Sotelo, Andreas Bender
Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes...
December 30, 2017: Journal of Cheminformatics
https://www.readbyqxmd.com/read/29274133/adenosine-a1-receptor-activates-background-potassium-channels-and-modulates-information-processing-in-olfactory-bulb-mitral-cells
#13
Natalie Rotermund, Svenja Winandy, Timo Fischer, Kristina Schulz, Torsten Fregin, Nadine Breitkreutz, Melanie Buchta, Janick Bartels, Mattias Carlström, Christian Lohr, Daniela Hirnet
Neuromodulation by adenosine is of critical importance in many brain regions, but the role of adenosine in olfactory information processing has not been studied so far. We investigated the effects of adenosine on mitral cells, which are projection neurons of the olfactory bulb. Significant expression of A1 and A2A receptors was found in mitral cells, as demonstrated by in situ hybridization. Application of adenosine in acute olfactory bulb slices hyperpolarized mitral cells in wild type, but not in adenosine A1 receptor knockout mice...
December 22, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29258235/gpcr-modulation-of-thieno-2-3-b-pyridine-anti-proliferative-agents
#14
Ayesha Zafar, Suat Sari, Euphemia Leung, Lisa I Pilkington, Michelle van Rensburg, David Barker, Jóhannes Reynisson
A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-b]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-δ1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible target, closely followed by tubulin...
December 18, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29250307/bitopic-fluorescent-antagonists-of-the-a2a-adenosine-receptor-based-on-pyrazolo-4-3-e-1-2-4-triazolo-1-5-c-pyrimidin-5-amine-functionalized-congeners
#15
Romain Duroux, Antonella Ciancetta, Philip Mannes, Jinha Yu, Shireesha Boyapati, Elizabeth Gizewski, Said Yous, Francisco Ciruela, John A Auchampach, Zhan-Guo Gao, Kenneth A Jacobson
A pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine antagonist of the A2A adenosine receptor (AR) was functionalized as amine congeners, fluorescent conjugates and a sulfonate, and the A2AAR binding modes were predicted computationally. The optimal n-butyl spacer was incorporated into the following A2AAR-selective (Ki, nM) conjugates: BODIPY630/650 derivative 11 (MRS7396, 24.6) and AlexaFluor488 derivative 12 (MRS7416, 30.3). Flow cytometry of 12 in hA2AAR-expressing HEK-293 cells displayed saturable binding (low nonspecific) and inhibition by known A2AAR antagonists...
August 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/29249971/inhibition-of-a2a-adenosine-receptor-signaling-in-cancer-cells-proliferation-by-the-novel-antagonist-tp455
#16
Stefania Gessi, Serena Bencivenni, Enrica Battistello, Fabrizio Vincenzi, Vittoria Colotta, Daniela Catarzi, Flavia Varano, Stefania Merighi, Pier Andrea Borea, Katia Varani
Several evidences indicate that the ubiquitous nucleoside adenosine, acting through A1, A2A, A2B, and A3 receptor (AR) subtypes, plays crucial roles in tumor development. Adenosine has contrasting effects on cell proliferation depending on the engagement of different receptor subtypes in various tumors. The involvement of A2AARs in human A375 melanoma, as well as in human A549 lung and rat MRMT1 breast carcinoma proliferation has been evaluated in view of the availability of a novel A2AAR antagonist, with high affinity and selectivity, named as 2-(2-furanyl)-N5-(2-methoxybenzyl)[1,3]thiazolo[5,4-d]pyrimidine-5,7-diammine (TP455)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29244203/pediatric-tolerogenic-dcs-expressing-cd4-and-immunoglobulin-like-transcript-receptor-ilt-4-secrete-il-10-in-response-to-fc-and-adenosine
#17
Alessandra Franco, Jeetendra Kumar, Gene Lin, Negar Behnamfar, Li-En Hisieh, Chisato Shimizu, Adriana H Tremoulet, Jane C Burns, Joel Linden
We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c+ CD11b+ CD14+ CD4+ and immunoglobulin-like transcript receptor (ILT)-4+ that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)-10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A2A receptor (A2A R), which, when activated by adenosine, inhibits the release of pro-inflammatory cytokines from most immune cells...
December 15, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29229601/a2ar-adenosine-signaling-suppresses-natural-killer-cell-maturation-in-the-tumor-microenvironment
#18
Arabella Young, Shin Foong Ngiow, Yulong Gao, Ann-Marie Patch, Deborah S Barkauskas, Meriem Messaoudene, Gene Lin, Jerome David Coudert, Kimberley A Stannard, Laurence Zitvogel, Mariapia A Degli-Esposti, Eric Vivier, Nicola Waddell, Joel Linden, Nicholas D Huntington, Fernando Souza-Fonseca Guimaraes, Mark J Smyth
Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs anti-tumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK cell-specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays...
December 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29223552/caffeine-rich-infusion-from-cola-nitida-kola-nut-inhibits-major-carbohydrate-catabolic-enzymes-abates-redox-imbalance-and-modulates-oxidative-dysregulated-metabolic-pathways-and-metabolites-in-fe2-induced-hepatic-toxicity
#19
Ochuko L Erukainure, Olajumoke A Oyebode, Mxolisi K Sokhela, Neil A Koorbanally, Md Shahidul Islam
The antioxidative and antidiabetic effects and toxicity of caffeine-rich infusion of Cola nitida were investigated using in vitro, ex vivo and in silico models. C. nitida was infused in boiling water and allowed to cool before concentrating at <50°C. HPLC analysis of the infusion revealed a caffeine content of 80.08%. The infusion showed potent in vitro antioxidant activity by significantly (p<0.05) scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH). It significantly (p<0.05) inhibited α-glucosidase and α-amylase activities...
December 6, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29217157/functional-histamine-h3-and-adenosine-a2a-receptor-heteromers-in-recombinant-cells-and-rat-striatum
#20
Ricardo Márquez-Gómez, Meridith T Robins, Citlaly Gutiérrez-Rodelo, Juan-Manuel Arias, Jesús-Alberto Olivares-Reyes, Richard M van Rijn, José-Antonio Arias-Montaño
In the striatum, histamine H3 receptors (H3Rs) are co-expressed with adenosine A2A receptors (A2ARs) in the cortico-striatal glutamatergic afferents and the GABAergic medium-sized spiny neurons that originate from the indirect pathway of the basal ganglia. This location allows H3Rs and A2ARs to regulate the striatal GABAergic and glutamatergic transmission. However, whether these receptors can physically interact has not yet been assessed. To test this hypothesis, a heteromer-selective in vitro assay was used to detect functional complementation between a chimeric A2AR302-Gαqi4 and wild-type H3Rs in transfected HEK-293 cells...
December 4, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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