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Karlnorbert Klotz - One of the best experts on this subject based on the ideXlab platform.
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novel 8 p substituted phenyl benzyl xanthines with selectivity for the a2a Adenosine Receptor possess bronchospasmolytic activity
European Journal of Medicinal Chemistry, 2014Co-Authors: Rakesh Yadav, Ranju Bansal, Sonja Kachler, Karlnorbert KlotzAbstract:A new series of 8-(p-substituted-phenyl/benzyl)xanthines has been synthesized and evaluated in vitro for Adenosine Receptor binding affinity and in vivo for bronchospasmolytic effects. It was observed that the nature of substituent at para-position of 8-phenyl/benzyl group on the xanthine scaffold remarkably affects the binding affinity and selectivity of xanthine derivatives for various Adenosine Receptor subtypes and also their bronchospasmolytic effects. Newly synthesized 8-phenylxanthines displayed potent binding affinity and significant selectivity for A2A Receptors and also produced potent bronchospasmolytic effects. Replacement of phenyl ring with benzyl moiety at C8 of xanthine skeleton resulted in notable reduction in Adenosine Receptor affinity and broncholytic effects.
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Receptor crosstalk haloperidol treatment enhances a 2a Adenosine Receptor functioning in a transfected cell model
Purinergic Signalling, 2010Co-Authors: Maria Letizia Trincavelli, Karlnorbert Klotz, Serena Cuboni, Mario Catena Dellosso, Roberto Maggio, Francesca Novi, Anna Panighini, Simona Daniele, Claudia MartiniAbstract:A2A Adenosine Receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A2A Adenosine Receptors are regulated by D2 dopamine Receptor ligands. These two Receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A2A Adenosine Receptor functional responses caused by the chronic blockade/activation of D2 dopamine Receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A2A Adenosine Receptors induced by antipsychotic drugs, commonly acting as D2 dopamine Receptor antagonists, in a cellular model co-expressing both A2A and D2 Receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A2A Receptor and also affected the degree of A2A–D2 Receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A2A Adenosine Receptor parameters, suggesting that the two classes of drugs have different effects on Adenosine–dopamine Receptor interaction. Modifications to A2A Adenosine Receptors may play a significant role in determining cerebral Adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A2A Adenosine Receptor ligands in pathologies associated with dopaminergic system dysfunction. Electronic supplementary material The online version of this article (doi:10.1007/s11302-010-9201-z) contains supplementary material, which is available to authorized users.
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the small antitumoral immune response modifier imiquimod interacts with Adenosine Receptor signaling in a tlr7 and tlr8 independent fashion
Journal of Investigative Dermatology, 2006Co-Authors: Michael P Schon, Margarete Schon, Karlnorbert KlotzAbstract:Imiquimod, a small-molecule immune response modifier of the imidazoquinoline family, has shown profound antitumoral and antiviral efficacy both in vitro and in clinical applications in vivo. It has been demonstrated that this activity is mediated through the Toll-like Receptor (TLR)7- and TLR8-signaling cascade resulting in the secretion of proinflammatory cytokines and, consecutively, induction of a tumor-directed cellular immune response. In addition, imiquimod exerts a direct proapoptotic activity in tumor cells. We demonstrate here that imiquimod induces activation of the transcription factor NF-κB and the downstream production of proinflammatory cytokines in the absence of TLR7 and TLR8. In Chinese hamster ovary cells stably transfected with the human Adenosine Receptor subtypes, we then show in radioligand-binding competition experiments that imiquimod binds to Adenosine Receptors at concentrations relevant in clinical settings, with highest affinities to the A1 and A2A subtypes. The effect on the Receptor-mediated activation of adenylyl cyclase was also studied, and these experiments revealed that imiquimod acts as an Adenosine Receptor antagonist. In addition, imiquimod had an inhibitory effect on adenylyl cyclase activity downstream from the Receptor. Finally, using transformed human keratinocytes, we provide experimental evidence that imiquimod and A2A Adenosine Receptor-specific compounds similarly induce proinflammatory cytokines in the absence of immune cells. Thus, imiquimod appears to suppress an important feedback mechanism of inflammation by antagonism of Adenosine Receptor-dependent increase of cAMP and a concomitant Receptor-independent inhibition of cAMP production. These novel mechanisms presumably act synergistic with the positive induction of proinflammatory cytokines and can, at least in part, explain the profound inflammation observed in some patients in vivo.
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water soluble phosphate prodrugs of 1 propargyl 8 styrylxanthine derivatives a2a selective Adenosine Receptor antagonists
Journal of Medicinal Chemistry, 2000Co-Authors: Roland Sauer, Karlnorbert Klotz, Juris Maurinsh, Ulrike Reith, Friederike Fulle, Christa E MullerAbstract:Water-soluble prodrugs of potent, A2A-selective Adenosine Receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxysty...
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8 sulfostyryl xanthines water soluble a2a selective Adenosine Receptor antagonists
Bioorganic & Medicinal Chemistry, 1998Co-Authors: Christa E Muller, Jesus Sandovalramirez, Ulrike Schobert, Uli Geis, Wolfram Frobenius, Karlnorbert KlotzAbstract:Abstract 8-(Sulfostyryl)xanthine derivatives were synthesized as water-soluble A2A-selective Adenosine Receptor (AR) antagonists. meta- and para-sulfostyryl-DMPX (3,7-dimethyl-1-propargylxanthine) derivatives 11a and 11b exhibited high affinity to rat A2A-AR in submicromolar concentrations, and were 20- to 30-fold selective versus rat A1-AR. Styryl-DMPX derivatives were inactive at human A2B- and A3-AR. 1,3-Dipropyl-8-p-sulfostyrylxanthine (13) and its 7-methyl derivative (14) showed similar (13) or higher (14) A2A affinity than 11a and 11b but showed no (13) or only a low degree (14) of selectivity versus A1-, A2B-, and A3-AR. The A2A-selective sulfostyryl-DMPX derivatives exhibit high water-solubility and may be useful research tools for in vivo studies.
Christa E Muller - One of the best experts on this subject based on the ideXlab platform.
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a2b Adenosine Receptor antagonists with picomolar potency
Journal of Medicinal Chemistry, 2019Co-Authors: Jie Jiang, Jorg Hockemeyer, Catharina Julia Seel, Ahmed Temirak, Vigneshwaran Namasivayam, Antonella Arridu, Jakub Schabikowski, Younis Baqi, Sonja Hinz, Christa E MullerAbstract:The A2B Adenosine Receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A2BAR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A2B-antagonist (Ki 0.0835 nM, KB 0.0598 nM, human A2BAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A2BAR, making it a promisi...
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xanthines as Adenosine Receptor antagonists
Handbook of experimental pharmacology, 2011Co-Authors: Christa E MullerAbstract:The natural plant alkaloids caffeine and theophylline were the first Adenosine Receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogues were subsequently synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes.
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water soluble phosphate prodrugs of 1 propargyl 8 styrylxanthine derivatives a2a selective Adenosine Receptor antagonists
Journal of Medicinal Chemistry, 2000Co-Authors: Roland Sauer, Karlnorbert Klotz, Juris Maurinsh, Ulrike Reith, Friederike Fulle, Christa E MullerAbstract:Water-soluble prodrugs of potent, A2A-selective Adenosine Receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxysty...
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8 sulfostyryl xanthines water soluble a2a selective Adenosine Receptor antagonists
Bioorganic & Medicinal Chemistry, 1998Co-Authors: Christa E Muller, Jesus Sandovalramirez, Ulrike Schobert, Uli Geis, Wolfram Frobenius, Karlnorbert KlotzAbstract:Abstract 8-(Sulfostyryl)xanthine derivatives were synthesized as water-soluble A2A-selective Adenosine Receptor (AR) antagonists. meta- and para-sulfostyryl-DMPX (3,7-dimethyl-1-propargylxanthine) derivatives 11a and 11b exhibited high affinity to rat A2A-AR in submicromolar concentrations, and were 20- to 30-fold selective versus rat A1-AR. Styryl-DMPX derivatives were inactive at human A2B- and A3-AR. 1,3-Dipropyl-8-p-sulfostyrylxanthine (13) and its 7-methyl derivative (14) showed similar (13) or higher (14) A2A affinity than 11a and 11b but showed no (13) or only a low degree (14) of selectivity versus A1-, A2B-, and A3-AR. The A2A-selective sulfostyryl-DMPX derivatives exhibit high water-solubility and may be useful research tools for in vivo studies.
Kenneth A Jacobson - One of the best experts on this subject based on the ideXlab platform.
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pharmacological and therapeutic effects of a3 Adenosine Receptor agonists
Drug Discovery Today, 2012Co-Authors: Pnina Fishman, Sara Baryehuda, Bruce T Liang, Kenneth A JacobsonAbstract:The A3 Adenosine Receptor (A3AR) coupled to Gi (inhibitory regulative guanine nucleotide-binding protein) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The Receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A3AR as a potential therapeutic target. Highly selective A3AR agonists have been synthesized and molecular recognition in the binding site has been characterized. In this article, we summarize preclinical and clinical human studies that demonstrate that A3AR agonists induce specific anti-inflammatory and anticancer effects through a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. At present, A3AR agonists are being developed for the treatment of inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis.
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structure of an agonist bound human a2a Adenosine Receptor
Science, 2011Co-Authors: Fei Xu, Kenneth A Jacobson, Vsevolod Katritch, Huixian Wu, Vadim Cherezov, Raymond C StevensAbstract:Activation of G protein–coupled Receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. We report the crystal structure of the A 2A Adenosine Receptor (A 2A AR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A 2A AR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V, and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A 2A AR and its ligand. The results define the molecule UK-432097 as a “conformationally selective agonist” capable of Receptor stabilization in a specific active-state configuration.
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DOI 10.5012/bkcs.2011.32.5.1620 Synthesis and Binding Affinity of Homologated Adenosine Analogues as A3 Adenosine Receptor Ligands
2011Co-Authors: Hyuk Woo Lee, Won Jun Choi, Kenneth A Jacobson, Lak Shin JeongAbstract:Homologated analogues 3a and 3b of potent and selective A3 Adenosine Receptor ligands, IB-MECA and dimethyl-IB-MECA were synthesized from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (4) via Co2(CO)8-catalyzed siloxymethylation as a key step. Unfortunately, homologated analogues 3a and 3b did not show significant binding affinities at three subtypes of Adenosine Receptors, indicating that free rotation, resulting from homologation, induced unfavorable interactions in the binding site of the Receptor maybe due to the presence of many conformations. Key Words: Co2(CO)8-catalyzed siloxymethylation, A3 Adenosine Receptor, Homologatio
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structure based discovery of a2a Adenosine Receptor ligands
Journal of Medicinal Chemistry, 2010Co-Authors: Jens Carlsson, Lena Yoo, Zhanguo Gao, John J Irwin, Brian K Shoichet, Kenneth A JacobsonAbstract:The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A2A Adenosine Receptor, based on complementarity to its recently determined structure. The A2A Adenosine Receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 μM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A2A versus the related A1 and A3 subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we at...
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Progress in the pursuit of therapeutic Adenosine Receptor antagonists.
Medicinal research reviews, 2006Co-Authors: Stefano Moro, Kenneth A Jacobson, Zhanguo Gao, Giampiero SpallutoAbstract:Ever since the discovery of the hypotensive and bradycardiac effects of Adenosine, Adenosine Receptors continue to represent promising drug targets. First, this is due to the fact that the Receptors are expressed in a large variety of tissues. In particular, the actions of Adenosine (or methylxanthine antagonists) in the central nervous system, in the circulation, on immune cells, and on other tissues can be beneficial in certain disorders. Second, there exists a large number of ligands, which have been generated by introducing several modifications in the structure of the lead compounds (Adenosine and methylxanthine), some of them highly specific. Four Adenosine Receptor subtypes (A1, A2A, A2B, and A3) have been cloned and pharmacologically characterized, all of which are G protein-coupled Receptors. Adenosine Receptors can be distinguished according to their preferred mechanism of signal transduction: A1 and A3 Receptors interact with pertussis toxin-sensitive G proteins of the Gi and Go family; the canonical signaling mechanism of the A2A and of the A2B Receptors is stimulation of adenylyl cyclase via Gs proteins. In addition to the coupling to adenylyl cyclase, all four subtypes may positively couple to phospholipase C via different G protein subunits. The development of new ligands, in particular, potent and selective antagonists, for all subtypes of Adenosine Receptors has so far been directed by traditional medicinal chemistry. The availability of genetic information promises to facilitate understanding of the drug-Receptor interaction leading to the rational design of a potentially therapeutically important class of drugs. Moreover, molecular modeling may further rationalize observed interactions between the Receptors and their ligands. In this review, we will summarize the most relevant progress in developing new therapeutic Adenosine Receptor antagonists.
John C Shryock - One of the best experts on this subject based on the ideXlab platform.
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regadenoson a selective a2a Adenosine Receptor agonist causes dose dependent increases in coronary blood flow velocity in humans
Journal of Nuclear Cardiology, 2007Co-Authors: Hsiao D Lieu, Gregory O Von Mering, Brent Blackburn, Ann Olmsted, Toufigh Gordi, John C Shryock, Luiz Belardinelli, Richard A KerenskyAbstract:Background Regadenoson is a selective A2A Adenosine Receptor agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging. This study characterized the dose dependence of regadenoson-induced coronary hyperemia.
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synthesis and biological effects of a new series of 2 amino 3 benzoylthiophenes as allosteric enhancers of a1 Adenosine Receptor
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Pier Giovanni Baraldi, John C Shryock, Francesca Fruttarolo, Abdel Naser Zaid, Ilaria Lampronti, Maria Giovanna Pavani, Mojgan Aghazadhe Tabrizi, Edward Leung, Romeo RomagnoliAbstract:New derivatives of PD 81,723, an allosteric enhancer of agonist binding to the A1-Adenosine Receptor, have been synthesized and evaluated in an intact cell assay. Compounds 3a, 3o and 3p appeared to be more potent than PD 81,723 and at a concentration of 0.1 microM caused significant reductions of cAMP content of CHO cells expressing the human A1-Adenosine Receptor. Compounds 4e and 4o appeared to be allosteric enhancers at a low concentration and antagonists at a higher concentration, whereas compounds 3c, 3g, 3s and 4l appeared to be weak antagonists that are also allosteric enhancers at the higher concentration of 10 microM.
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differential a1 Adenosine Receptor reserve for two actions of Adenosine on guinea pig atrial myocytes
Molecular Pharmacology, 1997Co-Authors: Miduturu Srinivas, John C Shryock, Donn M Dennis, Stephen P BakerAbstract:Adenosine activates Adenosine-induced inwardly rectifying K+ current (IKAdo) and inhibits isoproterenol (100 nM)-stimulated L-type Ca2+ current (beta-ICa,L) of guinea pig atrial myocytes with EC50 values of 2.17 and 0.20 microM, respectively. We determined whether this 11-fold difference in potency of Adenosine is due to the existence of a greater A1 Adenosine Receptor reserve for the inhibition of beta-ICa,L than for the activation of IKAdo. Atrial myocytes were pretreated with vehicle (control) or the irreversible A1 Adenosine Receptor antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxa nthine (FSCPX) (10 and 50 nM) for 30 min, and after a 60-min washout period, concentration-response curves were determined for the Adenosine-induced activation of IKAdo and inhibition of beta-ICa,L. Pretreatment of atrial myocytes with 10 nM FSCPX reduced the maximal activation of IKAdo by 60% (7.9 +/- 0.2 to 3.2 +/- 0.1 pA/pF). In contrast, a higher concentration of FSCPX (50 nM) was required to reduce the maximal inhibition of beta-ICa,L by 39% (95 +/- 4% to 58. 7 +/- 5.6%) and caused a 15-fold increase in the EC50 value of Adenosine. Values of the equilibrium dissociation constant (KA) for Adenosine to activate IKAdo and inhibit beta-ICa,L, estimated according to the method of Furchgott, were 2.7 and 5.6 microM, respectively. These values were used to determine the relationship between Adenosine Receptor occupancy and response. Half-maximal and maximal activations of IKAdo required occupancies of 40% and 98% of A1 Adenosine Receptors, respectively. In contrast, occupancies of only 4% and 70%, respectively, of A1 Adenosine Receptors were sufficient to cause half-maximal and maximal inhibitions of beta-ICa, L. Consistent with this result, a partial agonist of the A1 Adenosine Receptor SHA040 inhibited beta-ICa,L by 60 +/- 3.5% but activated IKAdo by only 18.1 +/- 2.5%. The results indicate that the A1 Adenosine Receptor is coupled more efficiently to an inhibition of beta-ICa,L than to an activation of IKAdo.
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a novel irreversible antagonist of the a1 Adenosine Receptor
Molecular Pharmacology, 1996Co-Authors: Miduturu Srinivas, John C Shryock, Peter J Scammells, Jackie Ruble, Stephen P BakerAbstract:We determined the effects of 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanth ine (FSCPX), a putative irreversible antagonist of the A1-Adenosine Receptor, on cardiac A1-Adenosine Receptor-mediated responses and on the specific binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX) to guinea pig cardiac and brain membranes. FSCPX (5 microM) completely reversed the increase in K+ current of guinea pig atrial myocytes caused by 100 microM Adenosine (259 +/- 30 to 20 +/- 7 pA) but had no significant effect on K+ currents caused by either 0.5 microM carbachol or 100 microM GTP gamma S. The attenuation of K+ current by FSCPX was both time and concentration dependent and persisted after washout of the antagonist. Pretreatment of atrial myocytes with FSCPX (50 nM) markedly attenuated the activation of K+ current and the inhibition of isoproterenol-stimulated I(Ca,L) caused by Adenosine by 90.1% and 84.2%, respectively, but did not alter the responses of atrial myocytes to carbachol. FSCPX (1 microM) irreversibly antagonized the A1-Adenosine Receptor-mediated increase in atrioventricular nodal conduction time of isolated perfused guinea pig hearts from 10.5 +/- 0.5 to 0.7 +/- 0.6 msec but did not significantly alter the A2-Adenosine Receptor-mediated decrease in coronary resistance. Preincubation of guinea pig cardiac membranes with 0.1, 1.0, or 3.0 microM FSCPX for 30 min reduced the Bmax of [3H]CPX binding by 41 +/- 10%, 67 +/- 6%, and 80 +/- 1% (mean +/- standard error, three experiments), respectively, with no significant change in the Kd. Similarly, 0.1 and 1.0 microM FSCPX irreversibly reduced the binding of [3H]CPX to guinea pig forebrain membranes by 65 +/- 5% and 83 +/- 2% (four experiments), respectively, but did not reduce the binding of [3H]CGS 21680, an A2a-Adenosine Receptor agonist, to striatal membranes. FSCPX did not affect the potency of 59-guanylylimidodiphosphate to inhibit the binding of [3H]CCPA, an A1-Adenosine Receptor agonist, to brain membranes. The results indicate that FSCPX is a specific, irreversible, A1-Adenosine subtype-selective Receptor antagonist.
Joel Linden - One of the best experts on this subject based on the ideXlab platform.
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the a2b Adenosine Receptor promotes th17 differentiation via stimulation of dendritic cell il 6
Journal of Immunology, 2011Co-Authors: Jeffrey M Wilson, Joel Linden, Courtney C Kurtz, Steven Black, William Ross, Mohammed S Alam, Peter B ErnstAbstract:Adenosine is an endogenous metabolite produced during hypoxia or inflammation. Previously implicated as an anti-inflammatory mediator in CD4(+) T cell regulation, we report that Adenosine acts via dendritic cell (DC) A(2B) Adenosine Receptor (A(2B)AR) to promote the development of Th17 cells. Mouse naive CD4(+) T cells cocultured with DCs in the presence of Adenosine or the stable Adenosine mimetic 5'-(N-ethylcarboximado) Adenosine resulted in the differentiation of IL-17- and IL-22-secreting cells and elevation of mRNA that encode signature Th17-associated molecules, such as IL-23R and RORγt. The observed response was similar when DCs were generated from bone marrow or isolated from small intestine lamina propria. Experiments using Adenosine Receptor antagonists and cells from A(2B)AR(-/-) or A(2A)AR(-/-)/A(2B)AR(-/-) mice indicated that the DC A(2B)AR promoted the effect. IL-6, stimulated in a cAMP-independent manner, is an important mediator in this pathway. Hence, in addition to previously noted direct effects of Adenosine Receptors on regulatory T cell development and function, these data indicated that Adenosine also acts indirectly to modulate CD4(+) T cell differentiation and suggested a mechanism for putative proinflammatory effects of A(2B)AR.
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the a2b Adenosine Receptor impairs the maturation and immunogenicity of dendritic cells
Journal of Immunology, 2009Co-Authors: Jeffrey M Wilson, Joel Linden, William Ross, Oma Agbai, Renea Frazier, Robert A Figler, Jayson M Rieger, Peter B ErnstAbstract:The endogenous purine nucleoside Adenosine is an important antiinflammatory mediator that contributes to the control of CD4(+) T cell responses. While Adenosine clearly has direct effects on CD4(+) T cells, it remains to be determined whether actions on APC such as dendritic cells (DC) are also important. In this report we characterize DC maturation and function in BMDC stimulated with LPS in the presence or absence of the nonselective Adenosine Receptor agonist NECA (5'-N-ethylcarboxamidoAdenosine). We found that NECA inhibited TNF-alpha and IL-12 in a concentration-dependent manner, whereas IL-10 production was increased. NECA-treated BMDC also expressed reduced levels of MHC class II and CD86 and were less effective at stimulating CD4(+) T cell proliferation and IL-2 production compared with BMDC exposed to vehicle control. Based on real-time RT-PCR, the A(2A) Adenosine Receptor (A(2A)AR) and A(2B)AR were the predominant Adenosine Receptors expressed in BMDC. Using Adenosine Receptor subtype selective antagonists and BMDC derived from A(2A)AR(-/-) and A(2B)AR(-/-)mice, it was shown that NECA modulates TNF-alpha, IL-12, IL-10, and CD86 responses predominantly via A(2B)AR. These data indicate that engagement of A(2B)AR modifies murine BMDC maturation and suggest that Adenosine regulates CD4(+) T cell responses by selecting for DC with impaired immunogencity.
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an a2a Adenosine Receptor agonist atl313 reduces inflammation and improves survival in murine sepsis models
BMC Infectious Diseases, 2008Co-Authors: Christopher C Moore, Edward N Martin, Tom G Obrig, Joel Linden, Michael W ScheldAbstract:Background The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A2A Adenosine Receptor (AR) agonist treated and untreated animals during experimental sepsis.
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a2b Adenosine Receptor gene deletion attenuates murine colitis
Gastroenterology, 2008Co-Authors: Vasantha L Kolachala, Joel Linden, Didier Merlin, Andrew T Gewirtz, Matam Vijay Kumar, G Dalmasso, Dan Yang, Lixin Wang, Katya Ravid, Shanthi V SitaramanAbstract:Background & Aims: The A2B Adenosine Receptor (A2BAR) is the predominant Adenosine Receptor expressed in the colonic epithelia. We have previously shown that A2BAR mRNA and protein levels are up-regulated during colitis. In this study, we addressed the role of the A2BAR in the development of murine colitis and the potential mechanism underlying its effects. Methods: Dextran sodium sulfate (DSS), 2,4,6-trinitrobenzene sulfonic acid (TNBS), and Salmonella typhimurium were used to induce colitis in A2BAR-null mice (A2BAR−/−). Colitis was determined using established clinical and histologic scoring. Keratinocyte-derived chemokine (KC) measurements were performed using an enzyme-linked immunosorbent assay. Results: Colonic inflammation induced by DSS, TNBS, or S typhimurium was attenuated in A2BAR−/− compared with their wild-type counterparts. Clinical features, histologic score, and myeloperoxidase activity were significantly decreased in A2BAR−/− mice. However, A2BAR−/− showed increased susceptibility to systemic Salmonella infection. Tissue levels of the neutrophil chemokine, KC was decreased in colitic A2BAR−/− mice. In addition, flagellin-induced KC levels were attenuated in A2BAR−/− mice. Neutrophil chemotaxis in response to exogenous interleukin-8 was preserved in A2BAR−/− mice, suggesting intact neutrophil migration in response to appropriate stimuli. Conclusions: These data demonstrate, for the first time, that the A2BAR plays a proinflammatory role in colitis. A2B Receptor antagonism may be an effective treatment for acute inflammatory intestinal diseases such as acute flare of inflammatory bowel disease.
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5 substituted 2 aminothiophenes as a1 Adenosine Receptor allosteric enhancers
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Luigi Aurelio, Joel Linden, Heidi Figler, Bernard L Flynn, Peter J ScammellsAbstract:Abstract Two series of 5-substituted 2-amino-4-(3-trifluoromethylphenyl)thiophenes were prepared and evaluated as allosteric enhancers at the A 1 Adenosine Receptor (A 1 AR). In the 3-benzoyl series, a 5-phenyl group was found to confer the greatest potency ( 9a : ED 50 = 2.1 μM, AE score = 18%). However, the analogue with no 5-substituent ( 6b : ED 50 = 15.8 μM, AE score = 77%) proved to be the most efficacious. In the 3-ethoxycarbonyl series, the 5-(4-chlorophenyl) analogue was clearly the most potent and efficacious ( 9l : ED 50 = 6.6 μM, AE score = 57%). The antagonist activity of all compounds was measured using a [ 3 H]CPX competitive binding assay.