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Shang, Liangcheng, Yaobiao Huang, Xin Xie, Sudan Ye, and Chun Chen. "Effect of Adenosine Receptor Antagonists on Adenosine-Pretreated PC12 Cells Exposed to Paraquat." Dose-Response 20, no. 2 (April 2022): 155932582210934. http://dx.doi.org/10.1177/15593258221093411.
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Previous studies evaluated the adenosine receptor antagonists alone to determine their effects on oxidative stress, but little is known about adenosine’s protective efficacy when oxidative injury occurs in vivo. Adenosine is a crucial signaling molecule recognized by four distinct G-protein-coupled receptors (GPCRs) (i.e., A1R, A2AR, A2BR, and A3R) and protects cells against pathological conditions. The present study was performed to evaluate the role of antagonist modulation in the setting of paraquat toxicity with adenosine pretreatment. First, PC12 cells were exposed to paraquat (850 μM) and adenosine (30 μM) to develop an in vitro model for the antagonist effect assay. Second, we found that the A1R antagonist DPCPX enhanced the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Moreover, the A2AR antagonist ZM241385 decreased the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Our findings indicate that adenosine protection requires a dual blockade of A1R and activation of A2AR to work at its full potential, and the A2B and A3 adenosine receptor antagonists increased paraquat-induced oxidative damage. This represents a novel pharmacological strategy based on A1/A2A interactions and can assist in clarifying the role played by AR antagonists in the treatment of neurodegenerative diseases.
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Shi, Yanrong, Xiaoguang Liu, Debebe Gebremedhin, John R. Falck, David R. Harder, and Raymond C. Koehler. "Interaction of Mechanisms Involving Epoxyeicosatrienoic Acids, Adenosine Receptors, and Metabotropic Glutamate Receptors in Neurovascular Coupling in Rat Whisker Barrel Cortex." Journal of Cerebral Blood Flow & Metabolism 28, no. 1 (May 23, 2007): 111–25. http://dx.doi.org/10.1038/sj.jcbfm.9600511.
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Adenosine, astrocyte metabotropic glutamate receptors (mGluRs), and epoxyeicosatrienoic acids (EETs) have been implicated in neurovascular coupling. Although A2A and A2B receptors mediate cerebral vasodilation to adenosine, the role of each receptor in the cerebral blood flow (CBF) response to neural activation remains to be fully elucidated. In addition, adenosine can amplify astrocyte calcium, which may increase arachidonic acid metabolites such as EETs. The interaction of these pathways was investigated by determining if combined treatment with antagonists exerted an additive inhibitory effect on the CBF response. During whisker stimulation of anesthetized rats, the increase in cortical CBF was reduced by approximately half after individual administration of A2B, mGluR and EET antagonists and EET synthesis inhibitors. Combining treatment of either a mGluR antagonist, an EET antagonist, or an EET synthesis inhibitor with an A2B receptor antagonist did not produce an additional decrement in the CBF response. Likewise, the CBF response also remained reduced by ∼50% when an EET antagonist was combined with an mGluR antagonist or an mGluR antagonist plus an A2B receptor antagonist. In contrast, A2A and A3 receptor antagonists had no effect on the CBF response to whisker stimulation. We conclude that (1) adenosine A2B receptors, rather than A2A or A3 receptors, play a significant role in coupling cortical CBF to neuronal activity, and (2) the adenosine A2B receptor, mGluR, and EETs signaling pathways are not functionally additive, consistent with the possibility of astrocytic mGluR and adenosine A2B receptor linkage to the synthesis and release of vasodilatory EETs.
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Bozarov, Andrey, Yu-Zhong Wang, Jun Ge Yu, Jacqueline Wunderlich, Hamdy H. Hassanain, Mazin Alhaj, Helen J. Cooke, Iveta Grants, Tianhua Ren, and Fievos L. Christofi. "Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 6 (December 2009): G1147—G1162. http://dx.doi.org/10.1152/ajpgi.00295.2009.
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We tested the novel hypothesis that endogenous adenosine (eADO) activates low-affinity A3 receptors in a model of neurogenic diarrhea in the guinea pig colon. Dimaprit activation of H2 receptors was used to trigger a cyclic coordinated response of contraction and Cl− secretion. Contraction-relaxation was monitored by sonomicrometry (via intracrystal distance) simultaneously with short-circuit current ( Isc, Cl− secretion). The short interplexus reflex coordinated response was attenuated or abolished by antagonists at H2 (cimetidine), 5-hydroxytryptamine 4 receptor (RS39604), neurokinin-1 receptor (GR82334), or nicotinic (mecamylamine) receptors. The A1 agonist 2-chloro- N6-cyclopentyladenosine (CCPA) abolished coordinated responses, and A1 antagonists could restore normal responses. A1-selective antagonists alone [8-cyclopentyltheophylline (CPT), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), or 8-cyclopentyl- N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-xanthine (FSCPX)] caused a concentration-dependent augmentation of crypt cell secretion or contraction and acted at nanomolar concentrations. The A3 agonist N6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide (IB-MECA) abolished coordinated responses and the A3 antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1191) could restore and further augment responses. The IB-MECA effect was resistant to knockdown of adenosine A1 receptor with the irreversible antagonist FSCPX; the IC50 for IB-MECA was 0.8 μM. MRS1191 alone could augment or unmask coordinated responses to dimaprit, and IB-MECA suppressed them. MRS1191 augmented distension-evoked reflex Isc responses. Adenosine deaminase mimicked actions of adenosine receptor antagonists. A3 receptor immunoreactivity was differentially expressed in enteric neurons of different parts of colon. After tetrodotoxin, IB-MECA caused circular muscle relaxation. The data support the novel concept that eADO acts at low-affinity A3 receptors in addition to high-affinity A1 receptors to suppress coordinated responses triggered by immune-histamine H2 receptor activation. The short interplexus circuit activated by histamine involves adenosine, acetylcholine, substance P, and serotonin. We postulate that A3 receptor modulation may occur in gut inflammatory diseases or allergic responses involving mast cell and histamine release.
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Muller, C. "A3 Adenosine Receptor Antagonists." Mini-Reviews in Medicinal Chemistry 1, no. 4 (November 1, 2001): 417–27. http://dx.doi.org/10.2174/1389557510101040417.
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Müller, Christa E. "A1-Adenosine receptor antagonists." Expert Opinion on Therapeutic Patents 7, no. 5 (May 1997): 419–40. http://dx.doi.org/10.1517/13543776.7.5.419.
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Pérez-Pinzón, Miguel A., Peter L. Lutz, Thomas J. Sick, and Myron Rosenthal. "Adenosine, a “Retaliatory” Metabolite, Promotes Anoxia Tolerance in Turtle Brain." Journal of Cerebral Blood Flow & Metabolism 13, no. 4 (July 1993): 728–32. http://dx.doi.org/10.1038/jcbfm.1993.93.
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Contrary to what is found in most vertebrates, the brains of certain turtle species maintain ATP levels and ion homeostasis and survive prolonged anoxia. The hypothesis tested here is that the release of adenosine and its binding to A1 receptors are essential for this anoxic tolerance. Studies were conducted in the isolated turtle cerebellum, which did release adenosine to the extracellular space during anoxia. When adenosine receptor antagonists [theophylline, 8-cyclopentyltheophylline (CPT), or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)] were added to the superfusate under control conditions, they had no effect on extracellular potassium ion activity ([K+]o). During anoxia, however, these antagonists provoked maximal efflux of K+ (anoxic depolarization). Anoxic depolarization occurred earlier during anoxia with theophylline (a nonspecific adenosine receptor antagonist) than with CPT or DPCPX, which specifically block A1 receptors. Therefore, adenosine release and effects mediated by A1 receptors are essential to anoxia tolerance in turtle brain.
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Temirak, Ahmed, Jonathan G. Schlegel, Jan H. Voss, Victoria J. Vaaßen, Christin Vielmuth, Tobias Claff, and Christa E. Müller. "Irreversible Antagonists for the Adenosine A2B Receptor." Molecules 27, no. 12 (June 13, 2022): 3792. http://dx.doi.org/10.3390/molecules27123792.
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Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a, PSB-21500) was the most potent and selective irreversible A2BAR antagonist of the present series with an apparent Ki value of 10.6 nM at the human A2BAR and >38-fold selectivity versus the other AR subtypes. The corresponding 3-cyclopropyl-substituted xanthine derivative 6c (PSB-21502) was similarly potent, but was non-selective versus A1- and A2AARs. Attachment of a reactive sulfonyl fluoride group to an elongated xanthine 8-substituent (12, Ki 7.37 nM) resulted in a potent, selective, reversibly binding antagonist. Based on previous docking studies, the lysine residue K2697.32 was proposed to react with the covalent antagonists. However, the mutant K269L behaved similarly to the wildtype A2BAR, indicating that 6a and related irreversible A2BAR antagonists do not interact with K2697.32. The new irreversible A2BAR antagonists will be useful tools and have the potential to be further developed as therapeutic drugs.
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Fan, Ming, Weixi Qin, and S. Jamal Mustafa. "Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 6 (June 1, 2003): L1012—L1019. http://dx.doi.org/10.1152/ajplung.00353.2002.
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We recently reported that adenosine caused bronchoconstriction and enhanced airway inflammation in an allergic mouse model. In this study, we further report the characterization of the subtype of adenosine receptor(s) involved in bronchoconstriction. 5′-( N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist, elicited bronchoconstriction in a dose-dependent manner. Little effects of N 6-cyclopentyladenosine (A1-selective agonist) and 2- p-(2-carboxyethyl)phenethylamino-5′- N-ethylcarboxamidoadenosine (A2A-selective agonist) compared with NECA were observed in this model. 2-Chloro- N 6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-β-d-ribofuranosyl]adenosine, an A3-selective receptor agonist, produced a dose-dependent bronchoconstrictor response, which was blocked by selective A3 antagonist 2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS1523). However, MRS1523 only partially inhibited NECA-induced bronchoconstriction. Neither selective A1 nor A2A antagonists affected NECA-induced bronchoconstriction. Enprofylline, a relatively selective A2B receptor antagonist, blocked partly NECA-induced bronchoconstriction. Furthermore, a combination of enprofylline and MRS1523 completely abolished NECA-induced bronchoconstrictor response. Using RT-PCR, we found that all four adenosine receptor subtypes are expressed in control lungs. Allergen sensitization and challenge significantly increased transcript levels of the A2B and A3receptors, whereas the A1 receptor message decreased. No change in transcript levels of A2A receptors was observed after allergen sensitization and challenge. These findings suggest that A2B and A3 adenosine receptors play an important role in adenosine-induced bronchoconstriction in our allergic mouse model. Finally, whether the airway effects of the receptor agonists/antagonists are direct or indirect needs further investigations.
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Baraldi, P. G., B. Cacciar, G. Spalluto, A. Borioni, M. Viziano, S. Dionisotti, and E. Ongini. "Current Developments of A2a Adenosine Receptor Antagonists." Current Medicinal Chemistry 2, no. 3 (October 1995): 707–22. http://dx.doi.org/10.2174/092986730203220223144628.
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<P>Adenosine regulates a wide range of physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four distinct adenosine receptors have been identified and classified as A1, A2a. A2b and A3. These adenosine receptors are members of the G-protein-coupled receptor family. <P> An intense medicinal chemistry effort made over the last 20 years has led to a variety of selective adenosine receptor agonists and antagonists. While all the agonists thus far identified are related to the adenosine structure, the antagonists available belong to different chemical classes. The prototypic antagonists are xanthine derivatives evolved from the natural compounds, caffeine and theophylline. Typically, they are 8-substituted-1,2,3-trialkylxanthine and are A1 selective antagonists. More recently, 8-styrylxanthines have been found to be selective for A2a receptors. Other non-xanthine heterocycles are potent A2a antagonists and possess different degree of selectivity. Selective antagonists are not available yet for A2b and A3 receptors. <P> Given the recent developments of A2a selective antagonists, we have reviewed their chemical structures and biological properties in the attempts to get insight into this emerging class of new interesting compounds. The development of some of the A2a antagonists will provide better understanding of the role of A2a receptors in physiological and pathological states. The compounds appear also to have the potential to be useful for the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease.</P>
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Tay, Apple Hui Min, Rubén Prieto-Díaz, Shiyong Neo, Le Tong, Xinsong Chen, Valentina Carannante, Björn Önfelt, et al. "A2B adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models." Journal for ImmunoTherapy of Cancer 10, no. 5 (May 2022): e004592. http://dx.doi.org/10.1136/jitc-2022-004592.
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BackgroundAdenosine is a metabolite that suppresses antitumor immune response of T and NK cells via extracellular binding to the two subtypes of adenosine-2 receptors, A2ARs. While blockade of the A2AARs subtype effectively rescues lymphocyte activity, with four A2AAR antagonists currently in anticancer clinical trials, less is known for the therapeutic potential of the other A2BAR blockade within cancer immunotherapy. Recent studies suggest the formation of A2AAR/A2BAR dimers in tissues that coexpress the two receptor subtypes, where the A2BAR plays a dominant role, suggesting it as a promising target for cancer immunotherapy.MethodsWe report the synthesis and functional evaluation of five potent A2BAR antagonists and a dual A2AAR/A2BAR antagonist. The compounds were designed using previous pharmacological data assisted by modeling studies. Synthesis was developed using multicomponent approaches. Flow cytometry was used to evaluate the phenotype of T and NK cells on A2BAR antagonist treatment. Functional activity of T and NK cells was tested in patient-derived tumor spheroid models.ResultsWe provide data for six novel small molecules: five A2BAR selective antagonists and a dual A2AAR/A2BAR antagonist. The growth of patient-derived breast cancer spheroids is prevented when treated with A2BAR antagonists. To elucidate if this depends on increased lymphocyte activity, immune cells proliferation, and cytokine production, lymphocyte infiltration was evaluated and compared with the potent A2AAR antagonist AZD-4635. We find that A2BAR antagonists rescue T and NK cell proliferation, IFNγ and perforin production, and increase tumor infiltrating lymphocytes infiltration into tumor spheroids without altering the expression of adhesion molecules.ConclusionsOur results demonstrate that A2BAR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for A2BAR blockade. Inhibition of A2BAR signaling restores T cell function and proliferation. Furthermore, A2BAR and dual A2AAR/A2BAR antagonists showed similar or better results than A2AAR antagonist AZD-4635 reinforcing the idea of dominant role of the A2BAR in the regulation of the immune system.
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Norton, Gavin R., Angela J. Woodiwiss, Robert J. McGinn, Mojca Lorbar, Eugene S. Chung, Thomas W. Honeyman, Richard A. Fenton, James G. Dobson, and Theo E. Meyer. "Adenosine A1receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 2 (February 1, 1999): H341—H349. http://dx.doi.org/10.1152/ajpheart.1999.276.2.h341.
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Presently, the physiological significance of myocardial adenosine A2a receptor stimulation is unclear. In this study, the influence of adenosine A2a receptor activation on A1 receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A2a receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10−8 M)-elicited contractile responses (+dP/d t max) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10−7 M), but not the selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10−7 M). The A2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (CGS-21680) at 10−5 M attenuated the antiadrenergic effect of the selective A1 receptor agonist 2-chloro- N 6-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 × 10−7 M)-elicited increases in intracellular Ca2+concentration ([Ca2+]i) transients but did not influence Iso-induced changes in [Ca2+]itransients in the absence of exogenous adenosine. These results indicate that adenosine A2areceptor antagonists enhance A1-receptor-induced antiadrenergic responses and that A2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A1 receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A2a receptors in the normal mammalian myocardium is to reduce A1 receptor-mediated antiadrenergic actions.
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PARSONS, WILLIAM J. "Methylxanthines as Adenosine Receptor Antagonists." Annals of Internal Medicine 103, no. 4 (October 1, 1985): 643. http://dx.doi.org/10.7326/0003-4819-103-4-643_1.
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Ongini, Ennio, Angela Monopoli, Barbara Cacciari, and Pier Giovanni Baraldi. "Selective adenosine A2A receptor antagonists." Il Farmaco 56, no. 1-2 (March 2001): 87–90. http://dx.doi.org/10.1016/s0014-827x(01)01024-2.
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Nadeem, Ahmed, and S. Jamal Mustafa. "Adenosine receptor antagonists and asthma." Drug Discovery Today: Therapeutic Strategies 3, no. 3 (September 2006): 269–75. http://dx.doi.org/10.1016/j.ddstr.2006.09.006.
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Khimenko, P. L., T. M. Moore, L. W. Hill, P. S. Wilson, S. Coleman, A. Rizzo, and A. E. Taylor. "Adenosine A2 receptors reverse ischemia-reperfusion lung injury independent of beta-receptors." Journal of Applied Physiology 78, no. 3 (March 1, 1995): 990–96. http://dx.doi.org/10.1152/jappl.1995.78.3.990.
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To evaluate the adenosine systems ability to reverse the endothelial damage produced by ischemia and reperfusion (I/R), we studied several different selective adenosine-receptor agonists and antagonists, a protein kinase A inhibitor, and a beta-adrenoreceptor antagonist in isolated buffer-perfused rat lungs. I/R (45 min/105 min) produced a sixfold increase in endothelial permeability as measured by the capillary filtration coefficient. Both a selective A2-receptor agonist (CGS-21680, 300 nM) and a beta-receptor agonist (isoproterenol, 10 microM) reversed the increased microvascular permeability. A nonselective adenosine-receptor antagonist (SPT, 20 microM) and a selective A1-receptor antagonist (DPCPX, 10 nM) had no effect on increased microvascular permeability. Also, isoproterenol and CGS-21680 reversed the damage being introduced after a selective A1-receptor agonist (CCPA, 100 nM). The nonspecific adenosine A1- and A2-receptor agonist NECA (12 nM) appeared to desensitize the A2 receptors and a protein kinase A inhibitor, adenosine-3′,5′-cyclic monophosphothioate (Rp-cAMPS, 100 microM), blocked the reversal of endothelial damage by isoproterenol or A2-receptor agonist. Propranolol (100 microM) blocked the effect of isoproterenol but not the effect of CGS-21680. From this study we conclude that A2-receptor activation reverses endothelial damage associated with I/R by a mechanism independent of beta-receptors or Gi protein. However, a protein kinase A-3′,5′,-cyclic adenosine monophosphate pathway is activated by both the adenosine systems and beta-receptor activation.
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Carlström, Mattias, Christopher S. Wilcox, and William J. Welch. "Adenosine A2 receptors modulate tubuloglomerular feedback." American Journal of Physiology-Renal Physiology 299, no. 2 (August 2010): F412—F417. http://dx.doi.org/10.1152/ajprenal.00211.2010.
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Adenosine can mediate the tubuloglomerular (TGF) response via activation of A1 receptors on the afferent arteriole, but both adenosine A1 and A2 receptors can regulate preglomerular resistance. We tested the hypothesis that adenosine A2 receptors offset the effect of A1 receptors and modulate the TGF. Maximal TGF responses were measured in male Sprague-Dawley rats as changes in proximal stop-flow pressure (ΔPSF) in response to increased perfusion of the loop of Henle (0 to 40 nl/min) with artificial tubular fluid (ATF). The maximal TGF response was studied after 5 min of intratubular perfusion (10 nl/min) with ATF alone, or with ATF plus the A2A receptor antagonist (ZM-241385; 10−7 or 10−5 mol/l), A1 receptor antagonist (PSB-36; 10−8 mol/l), or with a combination of A1 (PSB-36; 10−8 mol/l) and A2A (ZM-241385; 10−7 mol/l) antagonists. The maximal TGF response (ΔPSF) with ATF alone was 11.7 ± 1.0 mmHg. Specific A2 inhibition (low dose) enhanced the maximal TGF response (15.7 ± 0.8 mmHg; P < 0.01), whereas a high dose (unspecific inhibition) attenuated the response (5.0 ± 0.4 mmHg; P < 0.001). A1 inhibition alone led to a paradoxical TGF response, with an increase in PSF of 3.1 ± 0.5 mmHg ( P < 0.05). Simultaneous application of A1 and A2 antagonists abolished the TGF response (ΔPSF: 0.4 ± 0.3 mmHg). In conclusion, adenosine A2 receptors modulate the TGF response by counteracting the effects of adenosine A1 receptors.
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Jackson, Edwin K., Dongmei Cheng, Stevan P. Tofovic, and Zaichuan Mi. "Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1 receptor-mediated coincident signaling." American Journal of Physiology-Renal Physiology 302, no. 4 (February 15, 2012): F466—F476. http://dx.doi.org/10.1152/ajprenal.00495.2011.
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Adenosine A1 receptor antagonists have diuretic/natriuretic activity and may be useful for treating sodium-retaining diseases, many of which are associated with increased renal sympathetic tone. Therefore, it is important to determine whether A1 receptor antagonists alter renal sympathetic neurotransmission. In isolated, perfused rat kidneys, renal vasoconstriction induced by renal sympathetic nerve simulation was attenuated by 1) 1,3-dipropyl-8-p-sulfophenylxanthine (xanthine analog that is a nonselective adenosine receptor antagonist, but is cell membrane impermeable and thus does not block intracellular phosphodiesterases), 2) xanthine amine congener (xanthine analog that is a selective A1 receptor antagonist), 3) 1,3-dipropyl-8-cyclopentylxanthine (xanthine analog that is a highly selective A1 receptor antagonist), and 4) FK453 (nonxanthine analog that is a highly selective A1 receptor antagonist). In contrast, FR113452 (enantiomer of FK453 that does not block A1 receptors), MRS-1754 (selective A2B receptor antagonist), and VUF-5574 (selective A3 receptor antagonist) did not alter responses to renal sympathetic nerve stimulation, and ZM-241385 (selective A2A receptor antagonist) enhanced responses. Antagonism of A1 receptors did not alter renal spillover of norepinephrine. 2-Chloro- N6-cyclopentyladenosine (highly selective A1 receptor agonist) increased renal vasoconstriction induced by exogenous norepinephrine, an effect that was blocked by 1,3-dipropyl-8-cyclopentylxanthine, U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), PP1 (c-src inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), and OSU-03012 (3-phosphoinositide-dependent protein kinase-1 inhibitor). These results indicate that adenosine formed during renal sympathetic nerve stimulation enhances the postjunctional effects of released norepinephrine via coincident signaling and contributes to renal sympathetic neurotransmission. Likely, the coincident signaling pathway is: phospholipase C → protein kinase C → c-src → phosphatidylinositol 3-kinase → 3-phosphoinositide-dependent protein kinase-1.
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van Rensburg, HelenaDorathea Janse, LesetjaJ Legoabe, Gisella Terre’Blanche, and MiethaM Van der Walt. "2–Benzylidene–1–Indanone Analogues as Dual Adenosine A1/A2a Receptor Antagonists for the Potential Treatment of Neurological Conditions." Drug Research 69, no. 07 (January 7, 2019): 382–91. http://dx.doi.org/10.1055/a-0808-3993.
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AbstractPrevious studies explored 2-benzylidine-1-tetralone derivatives as innovative adenosine A1 and A2A receptor antagonists for alternative non-dopaminergic treatment of Parkinson’s disease. This study’s aim is to investigate structurally related 2-benzylidene-1-indanones with substitutions on ring A and B as novel, potent and selective adenosine A1 and A2A receptor blockers. 2-Benzylidene-1-indanone derivatives were synthesised via acid catalysed aldol condensation reactions and evaluated via radioligand binding assays to ascertain structure activity relationships to govern A1 and A2A AR affinity. The results indicated that hydroxy substitution at C4 of ring A and meta (3’), or para (4’) substitution on ring B of the 2-benzylidene-1-indanone scaffold (2c) is preferred over substitution at C5 (2d) or C6 (2e) of ring A for adenosine A1 receptor activity and selectivity in the micromolar range. Furthermore, substitution at the meta (3’) position of ring B with chlorine lead to the highly potent and selective adenosine A2A receptor antagonist, compound 2 h. Compound 2c and the 2q behaved as adenosine A1 receptor antagonists in the performed GTP shift assays. In view of these findings, compounds 2c, 2 h, 2q and 2p are potent and selective adenosine A1 and A2A receptor antagonists for the potential treatment of neurological conditions.
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Gorman, Mark W., Kayoko Ogimoto, Margaret V. Savage, Kenneth A. Jacobson, and Eric O. Feigl. "Nucleotide coronary vasodilation in guinea pig hearts." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 3 (September 2003): H1040—H1047. http://dx.doi.org/10.1152/ajpheart.00981.2002.
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The role of P1 receptors and P2Y1 receptors in coronary vasodilator responses to adenine nucleotides was examined in the isolated guinea pig heart. Bolus arterial injections of nucleotides were made in hearts perfused at constant pressure. Peak increase in flow was measured before and after addition of purinoceptor antagonists. Both the P1 receptor antagonist 8-( p-sulfophenyl)theophylline and adenosine deaminase inhibited adenosine vasodilation. AMP-induced vasodilation was inhibited by P1 receptor blockade but not by adenosine deaminase or by the selective P2Y1 antagonist N6-methyl-2′-deoxyadenosine 3′,5′-bisphosphate (MRS 2179). ADP-induced vasodilation was moderately inhibited by P1 receptor blockade and greatly inhibited by combined P1 and P2Y1 blockade. ATP-induced vasodilation was antagonized by P1 blockade but not by adenosine deaminase. Addition of P2Y1 blockade to P1 blockade shifted the ATP dose-response curve further rightward. It is concluded that in this preparation ATP-induced vasodilation results primarily from AMP stimulation of P1 receptors, with a smaller component from ATP or ADP acting on P2Y1 receptors. ADP-induced vasodilation is largely due to P2Y1 receptors, with a smaller contribution by AMP or adenosine acting via P1 receptors. AMP responses are mediated solely by P1 receptors. Adenosine contributes very little to vasodilation resulting from bolus intracoronary injections of ATP, ADP, or AMP.
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Mozaffari, Mahmood S., Worku Abebe, and Brett K. Warren. "Renal adenosine A3 receptors in the rat: assessment of functional role." Canadian Journal of Physiology and Pharmacology 78, no. 5 (April 10, 2000): 428–32. http://dx.doi.org/10.1139/y00-007.
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The functional roles of adenosine A3 receptors in the rat kidney were assessed for the first time with respect to A1 receptor-mediated responses. Utilizing a chronically instrumented conscious rat preparation, we tested renal excretory responses to acute administration of the A3 receptor antagonists 3-ethyl - 5-benzyl-2-methyl-6-phenyl- 4-phenylethynyl-1,4-(+)-dihydropridine-3,5-dicarboxylate (MRS-1191) and 9-chloro-2-(2-furyl)-5-phenylacetylamino- [1,2,4]-triazolo[1,5-c]quinazoline (MRS-1220) with reference to the effects of the A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The intravenous administration of DPCPX resulted in significant increases in fluid and sodium excretions without affecting glomerular filtration rate (GFR). This suggests that DPCPX-induced diuretic and natriuretic responses are related to decreased tubular reabsorption. However, neither MRS-1191 nor MRS-1220 alone affected fluid or sodium excretions, or GFR, indicating lack of an effect of either compound on renal function. On the other hand, the co-administration of MRS-1220 with DPCPX abolished both the diuretic and natriuretic responses to DPCPX, being suggestive of antagonism between these two compounds. MRS-1191, however, did not affect the DPCPX-induced fluid and sodium excretions. Neither the A1 nor the A3 receptor antagonists altered potassium excretion individually or in combination. The data suggest that while adenosine A1 receptors are involved in the regulation of renal fluid and sodium transport, A3 receptors do not appear to have a major role in regulation of renal excretory function under baseline physiological conditions. Key words: adenosine A3 receptor, adenosine antagonist, diuresis, natriuresis, rat.
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Carlsson, Per-Ola, Richard Olsson, Örjan Källskog, Birgitta Bodin, Arne Andersson, and Leif Jansson. "Glucose-induced islet blood flow increase in rats: interaction between nervous and metabolic mediators." American Journal of Physiology-Endocrinology and Metabolism 283, no. 3 (September 1, 2002): E457—E464. http://dx.doi.org/10.1152/ajpendo.00044.2002.
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This study investigated the mechanisms for glucose-induced islet blood flow increase in rats. The effects of adenosine, adenosine receptor antagonists, and vagotomy on islet blood flow were evaluated with a microsphere technique. Vagotomy prevented the islet blood flow increase expected 3, 10, and 20 min after injection of glucose, whereas theophylline (a nonspecific adenosine receptor antagonist) prevented the islet blood flow increase from occurring 10 and 20 min after glucose administration. Administration of selective adenosine receptor antagonists suggested that the response to theophylline was mediated by A1receptors. Exogenous administration of adenosine did not affect islet blood flow, but local accumulation of adenosine, induced by the adenosine uptake inhibitor dipyridamole, caused a doubling of islet blood flow. In conclusion, the increased islet blood flow seen 3 min after induction of hyperglycemia is caused by the vagal nerve, whereas the increase in islet blood perfusion seen at 10 and 20 min after glucose administration is caused by both the vagal nerve and adenosine.
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Bivalacqua, Trinity J., Hunter C. Champion, David G. Lambert, and Philip J. Kadowitz. "Vasodilator responses to adenosine and hyperemia are mediated by A1 and A2 receptors in the cat vascular bed." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 6 (June 1, 2002): R1696—R1709. http://dx.doi.org/10.1152/ajpregu.00394.2001.
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Hemodynamic responses to adenosine, the A1 receptor agonists N 6-cyclopentyladenosine (CPA) and adenosine amine congener (ADAC), and the A2 receptor agonist 5′-( N-cyclopropyl)-carboxamido-adenosine (CPCA) were investigated in the hindquarter vascular bed of the cat under constant-flow conditions. Injections of adenosine, CPA, ADAC, CPCA, ATP, and adenosine 5′- O-(3-thiotriphosphate) (ATPγS) into the perfusion circuit induced dose-related decreases in perfusion pressure. Vasodilator responses to the A1 agonists were reduced by the A1 receptor antagonists KW-3902 and CGS-15943, whereas responses to CPCA were reduced by the A2 antagonist KF-17837. Vasodilator responses to adenosine were reduced by KW-3902, CGS-15943, and by KF-17837, suggesting a role for both A1 and A2 receptors. Vasodilator responses to ATP and the nonhydrolyzable ATP analog ATPγS were not attenuated by CGS-15943 or KF-17837. After treatment with the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester, the cyclooxygenase inhibitor sodium meclofenamate, or the ATP-dependent K+ (K[Formula: see text]) channel antagonists U-37883A or glibenclamide, responses to adenosine and ATP were not altered. Responses to adenosine, CPA, and CPCA were increased in duration by rolipram, a type 4 cAMP phosphodiesterase inhibitor, but were not altered by zaprinast, a type 5 cGMP phosphodiesterase inhibitor. When blood flow was interrupted for a 30-s period, the magnitude and duration of the reactive vasodilator response were reduced by A1 and A2 receptor antagonists. These data suggest that vasodilator responses to adenosine and the A1and A2 agonists studied are not dependent on the release of cyclooxygenase products, nitric oxide, or the opening of K[Formula: see text] channels in the regional vascular bed of the cat. The present data suggest a role for cAMP in mediating responses to adenosine and suggest that vasodilator responses to adenosine and to reactive hyperemia are mediated in part by A1 and A2 receptors in the hindquarter vascular bed of the cat.
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Lorbar, Mojca, Eugene S. Chung, Arash Nabi, Katarina Skalova, Richard A. Fenton, James G. Dobson, Jr., and Theo E. Meyer. "Receptors subtypes involved in adenosine-mediated modulation of norepinephrine release from cardiac nerve terminals." Canadian Journal of Physiology and Pharmacology 82, no. 11 (November 1, 2004): 1026–31. http://dx.doi.org/10.1139/y04-108.
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The objective of this study was to determine which adenosine receptor subtypes were involved in the modulation of norepinephrine release from cardiac nerve terminals. In addition, the persistence of adenosine-mediated effects was evaluated. Rat hearts attached to the stellate ganglion were isolated and perfused. The ganglion was electrically stimulated twice (S1 and S2), allowing 10 min between the stimulations. To determine adenosine receptor subtypes, selective and nonselective adenosine agonists and antagonists were infused following S1 and until the end of S2. To evaluate the persistence of adenosine-mediated effect on norepinephrine release, the stellate ganglion was stimulated a third (S3) and fourth (S4) time. Coronary effluents were collected to determine norepinephrine content. Adenosine and a selective A1 receptor agonist, CCPA, inhibited norepinephrine release by 49% and 54%, respectively. This effect was reversed by simultaneous infusion of nonspecific (8-SPT) and specific (DPCPX) A1 receptor antagonists. Selective A2A (CGS 21680) and A3 (AB-MECA) receptor agonists had no discernible effect on norepinephrine release. Similarly, adenosine A2A receptor antagonists CSC and DMPX did not alter the dose-response relation between norepinephrine release and adenosine. Finally, the inhibitory effects of adenosine on norepinephrine release did not persist 10 min subsequent to the removal of adenosine. Adenosine inhibited norepinephrine release primarily via the adenosine A1 receptor. This effect of adenosine was of short duration. Adenosine A2A and A3 receptors were either absent or functionally insignificant in the regulation of norepinephrine release in the rat heart.Key words: adenosine, norepinephrine, receptor, rat, neurotransmitters.
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Gao, Zhan-Guo, and Kenneth A. Jacobson. "A2B Adenosine Receptor and Cancer." International Journal of Molecular Sciences 20, no. 20 (October 17, 2019): 5139. http://dx.doi.org/10.3390/ijms20205139.
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There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A2BAR, coupled to both Gαs and Gαi G proteins, is one of the several GPCRs that are expressed in a significantly higher level in certain cancer tissues, in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various cancers, and the rationale of using A2BAR antagonists in cancer therapy.
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Dubey, Raghvendra K., Delbert G. Gillespie, and Edwin K. Jackson. "A2B Adenosine Receptors Mediate the Anti-Mitogenic Effects of Adenosine in Cardiac Fibroblasts." Hypertension 36, suppl_1 (October 2000): 708. http://dx.doi.org/10.1161/hyp.36.suppl_1.708-b.
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P85 Adenosine inhibits growth of CFs; however, the adenosine receptor subtype that mediates this anti-mitogenic effect remains undefined. Using specific ADE receptor antagonists and agonists and antisense oligonucleotides (OLIGO) against A2B receptors, we investigated the role of A2B receptors in inhibiting cardiac fibroblast growth. PDGF (25ng/ml)-induced DNA synthesis, cell number and collagen synthesis in CFs were inhibited by A2 (chloroadenosine [Cl-Ad]and MECA), but not by A1 (CPA), A2a ( CGS21680 ) or A3 (AB-MECA),receptor agonists.The inhibitory effects of 1μM MECA and Cl-Ad were reversed by A1/A2 (DPSPX; 10nM), but not by A1 (DPCPX; 10nM), receptor antagonists. In CFs treated with antisense, but not sense or scrambled, OLIGOs to the A2B receptor, both basal and PDGF-induced DNA synthesis was enhanced by 70±4% and 64±5% respectively. Moreover, the inhibitory effects of Cl-Ad and MECA were completely abolished in CFs treated with antisense, but not sense and scrambled, OLIGOs. In conclusion, A2B receptors mediate the anti-mitogenic effects of adenosine suggesting that A2B receptors are importantly involved in the regulation of CF biology. Thus, A2B receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation.
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Marala, R. B., and S. J. Mustafa. "Adenosine analogues prevent phorbol ester-induced PKC depletion in porcine coronary artery via A1 receptor." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 1 (January 1, 1995): H271—H277. http://dx.doi.org/10.1152/ajpheart.1995.268.1.h271.
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This study was undertaken to determine the adenosine receptor involved in the modulation of protein kinase C (PKC) in porcine coronary artery. Endothelium-denuded arterial rings were incubated with phorbol 12,13-dibutyrate (PDBu) in the presence or absence of adenosine receptor agonists and antagonists for 24 h. After incubation, contractile responses to endothelin-1 (ET-1) were compared in various treatment groups. Arterial rings incubated with PDBu alone failed to produce significant contractions in response to ET-1. (2s)-N6-[2-endo-norbornyl]adenosine (ENBA), an A1-receptor agonist, attenuated the PDBu-induced blunting of the ET-1 contractions. Incubation with ENBA alone elevated ET-1 contractility by about twofold. Inclusion of A1-receptor antagonists completely blocked both effects of ENBA: protection against PDBu and increase in ET-1 contractility. On the contrary, arterial rings incubated with the A2-receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS-21680) did not show significant alteration of the ET-1 contractility when incubated with CGS-21680 alone or in combination with PDBu. Inclusion of A2-receptor antagonist in combination with CGS-21680 mimicked the effects of ENBA alone, i.e., protected against PDBu and enhanced ET-1 contractions. Measurement of PKC activities in arteries indicated that exposure to ENBA caused a twofold increase in the enzyme activity, whereas exposure to CGS-21680 had no significant effect on PKC activity. Adenosine analogues caused an accumulation of PKC through the activation of A1- but not A2-adenosine receptors. These results indicate that the modulation of PKC by adenosine analogues is mediated through A1-adenosine receptors in the coronary artery.
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Donoso, M. Verónica, Rodrigo López, Ramiro Miranda, René Briones, and J. Pablo Huidobro-Toro. "A2B adenosine receptor mediates human chorionic vasoconstriction and signals through arachidonic acid cascade." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 5 (May 2005): H2439—H2449. http://dx.doi.org/10.1152/ajpheart.00548.2004.
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Because adenosine is a vascular tone modulator, we examined the effect of adenosine and congeners in the vascular reactivity of isolated human placental vessels and in perfused cotyledons. We characterized its vasomotor action and tentatively identified the receptor subtypes and their intracellular signaling mechanisms. We recorded isometric tension from the circular layer of chorionic vessel rings maintained under 1.5 g of basal tension or precontracted with KCl. The relative order of potency of adenosine and structural analogs is consistent with the expression of A2B receptors, 5′-( N-ethylcarboxamido)adenosine (NECA) being the most potent. The maximal contraction ranged from 45% to 60% of the KCl standard response, except for an A2A receptor agonist that did not exceed 15%. Consistently, NECA was 100-fold more potent than adenosine to raise the perfusion pressure of ex vivo perfused cotyledons. In contrast, a selective A3 receptor agonist relaxed precontracted rings of chorionic vessels. Whereas a selective A3 receptor antagonist was ineffective to antagonize adenosine-induced contraction, A2 or A1 receptor antagonists reduced adenosine-induced vasoconstriction concentration-dependently. Denudation of the endothelial layer reduced adenosine- and NECA-induced contractions by 50–70%. Furthermore, indomethacin reduced adenosine- or NECA-induced contractions concentration-dependently in intact and endothelium-denuded rings. A thromboxane receptor antagonist blocked adenosine- and NECA-induced contractions in intact and endothelium-denuded rings, suggesting the involvement of an arachidonic acid metabolite as the mediator of the vasoconstriction. We propose that adenosine A2B receptors mediate the adenosine-induced contraction vasomotor effect in human chorionic vessels and that this involves synthesis of a thromboxane receptor activator or a related prostanoid.
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Bonaventura, Jordi, Gemma Navarro, Verònica Casadó-Anguera, Karima Azdad, William Rea, Estefanía Moreno, Marc Brugarolas, et al. "Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer." Proceedings of the National Academy of Sciences 112, no. 27 (June 22, 2015): E3609—E3618. http://dx.doi.org/10.1073/pnas.1507704112.
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Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.
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Jin, Jianguo, Todd M. Quinton, Jin Zhang, Susan E. Rittenhouse, and Satya P. Kunapuli. "Adenosine diphosphate (ADP)–induced thromboxane A2generation in human platelets requires coordinated signaling through integrin αIIbβ3 and ADP receptors." Blood 99, no. 1 (January 1, 2002): 193–98. http://dx.doi.org/10.1182/blood.v99.1.193.
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Adenosine diphosphate (ADP) is a platelet agonist that causes platelet shape change and aggregation as well as generation of thromboxane A2, another platelet agonist, through its effects on P2Y1, P2Y12, and P2X1 receptors. It is now reported that both 2-propylthio-D-βγ-dichloromethylene adenosine 5′-triphosphate (AR-C67085), a P2Y12 receptor–selective antagonist, and adenosine-2′-phosphate-5′-phosphate (A2P5P), a P2Y1 receptor–selective antagonist, inhibited ADP-induced thromboxane A2 generation in a concentration-dependent manner, indicating that coactivation of the P2Y12 and P2Y1 receptors is essential for this event. SC49992, a fibrinogen receptor antagonist, blocked ADP-induced platelet aggregation and thromboxane A2 production in a concentration-dependent manner. Similarly, P2 receptor antagonists or SC49992 blocked ADP-induced arachidonic acid liberation. Whereas SC49992 blocked arachidonic acid–induced platelet aggregation, it failed to inhibit thromboxane A2 generation induced by arachidonic acid. Thus, ADP-induced arachidonic acid liberation, but not subsequent conversion to thromboxane A2, requires outside-in signaling through the fibrinogen receptor. The Fab fragment of ligand-induced binding site–6 (LIBS6) antibody, which induces a fibrinogen-binding site on the integrin αIIbβ3, caused both platelet aggregation and thromboxane A2 generation. Inhibitors of phosphoinositide 3-kinase, Syk, Src kinases, or protein tyrosine phosphatases inhibited platelet aggregation but not thromboxane A2 generation, indicating that these signaling molecules have no significant role in phospholipase A2 activation. In the presence of P2 receptor antagonists A2P5P or AR-C67085, LIBS6 failed to generate thromboxane A2, suggesting that inside-out signaling through ADP receptors is necessary for this event. It was concluded that both outside-in signaling from the fibrinogen receptor and inside-out signaling from the P2Y1 and P2Y12 receptors are necessary for phospholipase A2 activation, resulting in arachidonic acid liberation and thromboxane A2 generation.
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Merighi, Stefania, Pier Andrea Borea, Katia Varani, Fabrizio Vincenzi, Alessia Travagli, Manuela Nigro, Silvia Pasquini, et al. "Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer’s Disease." Molecules 27, no. 9 (April 21, 2022): 2680. http://dx.doi.org/10.3390/molecules27092680.
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The A2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer’s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A2A adenosine receptors in AD animal and human studies and reports the state of the art of A2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood–brain barrier in the discovery of new agents for treating CNS disorders. Considering that A2A receptor antagonist istradefylline is already commercially available for Parkinson’s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.
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Neely, C. F., J. Jin, and I. M. Keith. "A1-adenosine receptor antagonists block endotoxin-induced lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 272, no. 2 (February 1, 1997): L353—L361. http://dx.doi.org/10.1152/ajplung.1997.272.2.l353.
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Endotoxin produces a variety of biological effects on different cell types, such as priming of neutrophils and macrophages, which then release a number of important mediators of endotoxin-induced lung injury. However, the specific mechanism by which endotoxin initiates its cascade of pathophysiological events in the lung has not been described. Both A1 adenosine receptor activation and endotoxin induce the release of thromboxane A2 from the lung and inhibit adenylate cyclase. By acting on A1 adenosine receptors, adenosine promotes neutrophil chemotaxis and adherence to endothelial cells. We hypothesized that A1 adenosine receptor activation is essential to endotoxin-induced lung injury, and we used the highly selective A1-adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-benzyl-7,[2-[ethyl(2-hydroxyethyl)amino]-ethyl] theophylline (bamiphylline), to investigate whether selective blocking of the A1 adenosine receptor would prevent endotoxin-induced acute lung injury. An intralobar arterial infusion of endotoxin (15 mg/kg) into the left lower lobe of the lung in intact-chest, spontaneously breathing cats produced lung injury characterized by the presence of neutrophils, macrophages, and red blood cells (RBCs) in alveoli, and alveolar edema and necrosis. Lower doses of endotoxin (5 or 10 mg/kg) produced less severe and dose-dependent lung injury. Endotoxin (15 mg/kg)-induced alveolar injury was blocked in a highly significant manner by A1-adenosine receptor antagonists, DPCPX and bamiphylline. An intravenous bolus of DPCPX 30 min before endotoxin infusion or a continuous intravenous infusion of bamiphylline 30 min before, during, and 30 min after endotoxin reduced the percent injured alveoli (defined as the presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 57 +/- 31% (endotoxin 15 mg/kg) to 9 +/- 1% (DPCPX) or 21 +/- 14% (bamiphylline), which were not significantly different from control (1-h perfusion only) (4 +/- 1%) (P < 0.05). These data represent the first evidence that A1-adenosine receptor antagonism blocks the capacity of endotoxin to cause lung injury. A1-adenosine receptor antagonists may be useful in preventing adult respiratory distress syndrome associated with septicemia.
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Monahan, Thomas S., Darrell R. Sawmiller, Richard A. Fenton, and James G. Dobson. "Adenosine A2a-receptor activation increases contractility in isolated perfused hearts." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 4 (October 1, 2000): H1472—H1481. http://dx.doi.org/10.1152/ajpheart.2000.279.4.h1472.
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Adenosine A2a-receptor activation enhances shortening of isolated cardiomyocytes. In the present study the effect of A2a-receptor activation on the contractile performance of isolated rat hearts was investigated by recording left ventricular pressure (LVP) and the maximal rate of LVP development (+dP/d t max). With constant-pressure perfusion, adenosine caused concentration-dependent increases in LVP and +dP/d t max, with detectable increases of 4.1 and 4.8% at 10−6 M and maximal increases of 12.0 and 11.1% at 10−4 M, respectively. The contractile responses were prevented by the A2a-receptor antagonists chlorostyryl-caffeine and aminofuryltriazolotriazinyl-aminoethylphenol (ZM-241385) but were not affected by the β1-adrenergic antagonist atenolol. The adenosine A1-receptor antagonist dipropylcyclopentylxanthine and pertussis toxin potentiated the positive inotropic effects of adenosine. The A2a-receptor agonists ethylcarboxamidoadenosine and dimethoxyphenyl-methylphenylethyl-adenosine also enhanced contractility. With constant-flow perfusion, 10−5 M adenosine increased LVP and +dP/d t max by 5.5 and 6.0%, respectively. In the presence of the coronary vasodilator hydralazine, adenosine increased LVP and +dP/d t max by 7.5 and 7.4%, respectively. Dipropylcyclopentylxanthine potentiated the adenosine contractile responses with constant-flow perfusion in the absence and presence of hydralazine. These increases in contractile performance were also antagonized by chlorostyryl-caffeine and ZM-241385. The results indicate that adenosine increases contractile performance via activation of A2a receptors in the intact heart independent of β1-adrenergic receptor activation or changes in coronary flow.
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Chen, J., B. Dinger, and S. J. Fidone. "cAMP production in rabbit carotid body: role of adenosine." Journal of Applied Physiology 82, no. 6 (June 1, 1997): 1771–75. http://dx.doi.org/10.1152/jappl.1997.82.6.1771.
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Chen, J., B. Dinger, and S. J. Fidone. cAMP production in rabbit carotid body: role of adenosine. J. Appl. Physiol. 82(6): 1771–1775, 1997.—In the present study, we have investigated the possible role of adenosine in the hypoxia-mediated increase in adenosine 3′,5′-cyclic monophosphate (cAMP) in the carotid body. cAMP levels in rabbit carotid bodies superfused in vitro for 10 min were increased in the presence of adenosine (100 μM and 1.0 mM; maximum increase = 127%, P < 0.01). These effects were reduced by the nonspecific adenosine-receptor antagonist 1,3-dipropyl-8[ p-sulfophenyl]xanthine (DPSPX; 10 μM). The specific A2-receptor agonist 2-[4′(2-carboxymethyl)phenylethylamino]-5′- N-ethylcarboxamido adenosine (CGS-21680; 100 nM) also elevated carotid body cAMP levels, an effect that was blocked by the specific A2-antagonist 3,7-dimethyl-l-propargyl-xanthine (DMPX; 50 μM). Hypoxia-evoked elevations in cAMP were potentiated in the presence of the adenosine-uptake inhibitor dipyridamole (100 nM) and blocked by exposure to adenosine-receptor antagonists. Our data suggest that the rabbit carotid body contains specific adenosine receptors (A2 subtype) that are positively coupled to adenylate cyclase and that increases in cAMP associated with hypoxia are mediated by the release of endogenous adenosine.
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Cacciari, Barbara, Giorgia Pastorin, Chiara Bolcato, Giampiero Spalluto, Magdalena Bacilieri, and Stefano Moro. "A2B Adenosine Receptor Antagonists: Recent Developments." Mini-Reviews in Medicinal Chemistry 5, no. 12 (December 1, 2005): 1053–60. http://dx.doi.org/10.2174/138955705774933374.
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Roy, Kunal. "QSAR of Adenosine Receptor Antagonists II:." QSAR & Combinatorial Science 22, no. 6 (August 2003): 614–21. http://dx.doi.org/10.1002/qsar.200330821.
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Cheong, Siew Lee, Gopalakrishnan Venkatesan, Priyankar Paira, Ramasamy Jothibasu, Alexander Laurence Mandel, Stephanie Federico, Giampiero Spalluto, and Giorgia Pastorin. "Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships." International Journal of Medicinal Chemistry 2011 (April 7, 2011): 1–15. http://dx.doi.org/10.1155/2011/480652.
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In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3) has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR) profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.
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Shultz, P. J., J. R. Sedor, and H. E. Abboud. "Dopaminergic stimulation of cAMP accumulation in cultured rat mesangial cells." American Journal of Physiology-Heart and Circulatory Physiology 253, no. 2 (August 1, 1987): H358—H364. http://dx.doi.org/10.1152/ajpheart.1987.253.2.h358.
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Dopamine (DA) alters renal hemodynamics, and DA receptors have been demonstrated in isolated glomeruli. To determine the glomerular cell type bearing DA receptors, we studied the effect of dopaminergic agonists and antagonists on adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in rat glomerular mesangial and epithelial cells in culture. DA caused a marked dose- and time-dependent increase in cAMP accumulation in mesangial but not epithelial cells. The stimulatory effect of DA was abolished by the DA antagonists haloperidol, trifluoperazine, and cis-thiothixene but not by beta- or alpha-adrenergic or histamine antagonists. Similar to the effects of DA, two dopamine type I receptor agonists, fenoldopam and SKF 38393, markedly stimulated cAMP accumulation in the mesangial cells. Moreover, the effects of DA were blocked by Sch 23390, a specific DA1 receptor antagonist, but not domperidone, a specific DA2 antagonist. These results show that DA regulates cAMP accumulation in mesangial cells via DA1-type receptors.
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Thümmler, Susanne, and Thomas V. Dunwiddie. "Adenosine Receptor Antagonists Induce Persistent Bursting in the Rat Hippocampal CA3 Region Via an NMDA Receptor-Dependent Mechanism." Journal of Neurophysiology 83, no. 4 (April 1, 2000): 1787–95. http://dx.doi.org/10.1152/jn.2000.83.4.1787.
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Adenosine receptor antagonists initiate repetitive bursting activity in the CA3 region of hippocampal slices. Although some studies have suggested that this effect is irreversible, this has been difficult to establish because many adenosine antagonists wash out of brain slices extremely slowly. Furthermore the cellular mechanism that underlies persistent bursting is unknown. To resolve these issues, we studied the effects of nonselective (8-p-sulfophenyltheophylline, 8SPT, 50–100 μM), Al-selective (8-cyclopentyl-1,3-dipropylxanthine, 100 nM; xanthine carboxylic acid congener, 200 nM), and A2A-selective (chlorostyryl-caffeine; 200 nM) adenosine antagonists in the CA3 region of rat hippocampal slices using extracellular recording. Superfusion with all of the adenosine antagonists except chlorostyryl-caffeine induced bursting, and the burst frequency after 30 min drug superfusion did not differ for the different antagonists. Most slices showed a period of rapid initial bursting, followed either by stable bursting at a lower frequency or a pattern of oscillating burst frequency. In either case, the bursting continued after drug washout. Virtually identical patterns of long-term bursting activity were observed when 8SPT was washed out or applied continuously. Control experiments using exogenous adenosine to characterize the persistence of 8SPT in tissue demonstrated >95% washout at 60 min, a time when nearly all slices still showed regular bursting activity. When the N-methyl-d-aspartate (NMDA) antagonistsdl−2-amino-5-phosphonovaleric acid (AP5; 50 μM) or dizocilpine (10 μM) were applied before and during 8SPT superfusion, bursting occurred in the presence of the NMDA antagonists but did not persist once the 8SPT was washed out. AP5 had no effect on persistent bursting when applied after the initiation of spiking. The selective calcium/calmodulin-dependent protein kinase inhibitor 1-[ N,O- bis-(5-isoquinolinesulfonyl)- N-methyl-l-tyrosyl]-4-phenylpiperazine (KN-62; 3 μM), which has been shown to block NMDA receptor-dependent synaptic plasticity in the CA1 region, also significantly decreased the long-term effect of 8SPT. Thus adenosine antagonists initiate persistent spiking in the CA3 region; this activity does not depend on continued occupation of adenosine receptors by antagonists, and can be blocked by treatments that prevent NMDA receptor-dependent plasticity.
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Coulson, R., P. S. Proch, R. A. Olsson, C. E. Chalfant, and D. R. Cooper. "Upregulated renal adenosine A1 receptors augment PKC and glucose transport but inhibit proliferation." American Journal of Physiology-Renal Physiology 270, no. 2 (February 1, 1996): F263—F274. http://dx.doi.org/10.1152/ajprenal.1996.270.2.f263.
Full textAbstract:
Adenosine A1 receptor densities were increased in cultured LLC-PK1 and OK cells by chronic treatment with the adenosine receptor antagonists 1,3,7-trimethylxanthine (caffeine, 1 mM) and 1,3-dimethyl-8-cyclopentylxanthine [cyclopentyltheophylline (CPT), < or = 0.4 mM], respectively. The A1 receptor number per cell was increased twofold by 10-day treatments with 1 mM caffeine or 0.1 mM CPT, and the sodium-coupled glucose uptake was augmented twofold by 1 mM caffeine and sevenfold by 0.1 microM CPT (higher doses of CPT were progressively less stimulatory). Glucose uptake was blocked by acute (2-h) treatment with CPT, adenosine deaminase, or calphostin C. Caffeine (1 mM) or CPT (> or = 0.1 mM) inhibited cell proliferation for the first 10 days, then cell growth assumed a normal proliferative rate despite continued presence of antagonist. Cytosolic protein kinase C (PKC) beta-isoform immunoactivity and PKC-beta II mRNA were elevated at least twofold during 10 days of 0.1 mM CPT or 1 mM caffeine treatment. The sustained elevation in sodium-glucose symport and PKC activity observed with adenosine receptor antagonists was similar to acute (2-h) effects of the adenosine A1 agonist R(-)-N6-phenylisopropyladenosine (R-PIA, 0.1-1 microM). Moreover, cell proliferation was increased by adenosine (0.1 microM R-PIA), whereas Na-K-adenosinetriphosphatase activity was unaltered with chronic antagonist or acute adenosine treatments. Caffeine treatment may have some non-adenosine A1 receptor-mediated actions, because it slightly (30%) augmented protein kinase A activity. It is concluded that chronic exposure of proximal tubule cells to caffeine or CPT augments PKC and sodium-glucose transport but retards cell proliferation mainly via adenosine A1 receptor-mediated mechanisms.
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Castaldo, C., T. Benicchi, M. Otrocka, E. Mori, E. Pilli, P. Ferruzzi, S. Valensin, et al. "CXCR4 Antagonists." Journal of Biomolecular Screening 19, no. 6 (March 14, 2014): 859–69. http://dx.doi.org/10.1177/1087057114526283.
Full textAbstract:
The CXC chemokine receptor 4 (CXCR4) is a widely expressed G protein–coupled receptor implicated in several diseases. In cancer, an increased number of surface CXCR4 receptors, in parallel with aberrant signaling, have been reported to influence several aspects of malignancy progression. CXCR4 activation by the specific ligand C-X-C motif chemokine 12 (CXCL12) induces several intracellular signaling pathways that have been selectively related to malignancy depending on the tissue or cell type. We developed a panel of CXCR4 screening assays investigating Gαi-mediated cyclic adenosine monophosphate modulation, β-arrestin recruitment, and receptor internalization. All of the assays were set up in recombinant cells and were used to test four reported CXCR4 antagonists. Consequently, a set of hit compounds, deriving from a screening campaign of a 30,000-small-molecule internal library, was profiled with the different assays. We identified several compounds showing a pathway-selective activity: antagonists on a Gαi-dependent pathway; antagonists on both the β-arrestin and Gαi-dependent pathways, some of which induce receptor internalization; and compounds with an antagonist behavior in all of the readouts. The identified biased antagonists induce different functional states on CXCR4 and preferentially affect specific downstream responses from the activated receptor, thus providing an improved therapeutic profile for correction of CXCR4 abnormal signaling.
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Schepp, W., A. H. Soll, and J. H. Walsh. "Dual modulation by adenosine of gastrin release from canine G-cells in primary culture." American Journal of Physiology-Gastrointestinal and Liver Physiology 259, no. 4 (October 1, 1990): G556—G563. http://dx.doi.org/10.1152/ajpgi.1990.259.4.g556.
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The effects of adenosine on gastrin release were studied in enzymatically dispersed canine antral cells after 24-36 h in primary culture. We found two contrasting actions for adenosine: inhibition of forskolin-stimulated gastrin release and potentiation of bombesin-stimulated gastrin release. These actions appeared to be mediated by A1 and A2 receptors, respectively. Forskolin-stimulated gastrin release was reduced by adenosine and the A1-selective agonist N6-(L-2-phenylisopropyl)adenosine (L-PIA) but not by the A2-selective agonist 2-phenylaminoadenosine (CV 1808). This inhibition by adenosine was reversed by the preferential A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) as well as by the nonselective adenosine receptor antagonist 8-phenyltheophylline (8-PT). Incubation of the cells with pertussis toxin (200 ng, 8 h) reversed the inhibition by adenosine. In contrast, bombesin stimulation of gastrin release was potentiated by adenosine and CV 1808 but not altered by L-PIA. This effect was enhanced by DPCPX and was not altered by treatment of cells with pertussis toxin. In the absence of exogenous adenosine, 8-PT and DPCPX produced a small increase in basal and stimulated gastrin release. These data suggest dual modulation by adenosine of G-cell function. A1 receptors inhibit adenosine 3,5'-cyclic monophosphate (cAMP)-mediated gastrin release via a pertussis toxin-sensitive mechanism, whereas A2 receptors potentiated the response to cAMP-independent stimuli of gastrin release. Enhancement of gastrin release by adenosine antagonists suggests functional restraint by endogenous adenosine.
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Glenn, Jackie, Ann White, Sue Fox, Hans van Giezen, Sven Nylander, Stan Heptinstall, and David Iyú. "Mode of action of P2Y12 antagonists as inhibitors of platelet function." Thrombosis and Haemostasis 105, no. 01 (2011): 96–106. http://dx.doi.org/10.1160/th10-07-0482.
Full textAbstract:
SummaryP2Y12 receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y12 receptors. However, some P2Y12 receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y12 antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y12 receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A2A agonists, which act at Gs-coupled receptors. All three P2Y12 antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A2 mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y12 antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the Gs-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y12 antagonists acting through PAR1, TP, IP, EP4, A2A or EP3 receptors. All three P2Y12 antagonists enhanced VASPphosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y12 receptors and not through another G-protein-coupled receptor.
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Auchampach, J. A., and G. J. Gross. "Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 5 (May 1, 1993): H1327—H1336. http://dx.doi.org/10.1152/ajpheart.1993.264.5.h1327.
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The objective of the present study was to characterize the role of adenosine in myocardial ischemic preconditioning in the canine heart. Preconditioning with 5 min of ischemia resulted in a marked reduction in infarct size after 60 min of left circumflex coronary artery occlusion and 5 h of reperfusion in barbital-anesthetized dogs compared with dogs that were not preconditioned (4.8 +/- 1.9 vs. 27.9 +/- 4.5%; P < 0.05). Pretreatment with either the nonselective adenosine receptor antagonist PD 115199 or the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked this protective effect, although in the absence of preconditioning neither of the antagonists affected infarct size. Intracoronary infusion of two different doses of adenosine or dipyridamole over a 5-min period before a prolonged 60-min occlusion period did not mimic preconditioning; however, intracoronary infusion of a combination of adenosine and dipyridamole produced a significant reduction in infarct size (13.6 +/- 4.1%), which was abolished by pretreatment with the ATP-dependent potassium (KATP) channel antagonist glibenclamide. These results suggest that activation of adenosine A1 receptors produces myocardial preconditioning in the canine heart by opening KATP channels.
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Pan, Sheng-Jun, and Li-Rong Li. "Adenosine A2 receptors are involved in the activation of ATP-sensitive K+ currents during metabolic inhibition in guinea pig ventricular myocytes." Canadian Journal of Physiology and Pharmacology 89, no. 3 (March 2011): 187–96. http://dx.doi.org/10.1139/y11-010.
Full textAbstract:
It has been hypothesized that an interaction among adenosine A1 receptors, protein kinase C (PKC) activation, and ATP-sensitive potassium channels (KATP) mediates ischemic preconditioning in experiments on different animal species. The purpose of this study was to determine if activation of KATP is functionally coupled to A1 receptors and (or) PKC activation during metabolic inhibition (MI) in guinea pig ventricular myocytes. Perforated-patch using nystatin and conventional whole-cell recording methods were used to observe the effects of adenosine and adenosine-receptor antagonists on the activation of KATP currents during MI induced by application of 2,4-dinitrophenol (DNP) and 2-deoxyglucose (2DG) without glucose, in the presence or absence of a PKC activator, phorbol 12-myristate 13-acetate (PMA). Adenosine accelerated the time course activation of KATP currents during MI under the intact intracellular condition or dialyzed condition with l mmol/L ATP in the pipette solution. The accelerated effect of adenosine activation of KATP under MI was not reversed by a nonselective Al adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (SPT), or a specific Al adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). However, the adenosine A2 receptor antagonist alloxazine reversed the time course activation of the KATP current under MI. An adenylate cyclase activator, forskolin, did not further abbreviate the time course activation of KATP with or without adenosine. Application of a PKC blocker, chelerythrine, reversed the time course activation of KATP by adenosine under MI. In addition, pretreatment with a PKC activator, PMA, had similar effects to adenosine, while adenosine did not further shorten the time required for activation of KATP currents during MI with PMA pretreatment. There is no direct evidence of activation of KATP currents by adenosine A1 receptor during metabolic inhibition under our experimental condition. However, adenosine A2 receptor activation is involved in the KATP channel activation in the guinea pig ventricular myocytes, of which effect is not mediated through the increase in intracellular cAMP. Adenosine seems to interact with PKC activation to open KATP during MI, but a possible link between the adenosine A2 receptor and PKC activation in this process needs further elucidation.
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LIU, Chengqian, Yulia Mukienko, Chengxiang Wu, and Andrey Zavialov. "Human adenosine deaminases control the immune cell responses to activation signals by reducing extracellular adenosine concentration." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 124.63. http://dx.doi.org/10.4049/jimmunol.196.supp.124.63.
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Abstract Adenosine rapidly accumulates in the sites of inflammation and tumor growth. It binds to adenosine receptors expressed on the cell surface of immune cells and induces either suppression or activation of inflammatory responses to pathogens. In humans the level of extracellular adenosine is regulated by two adenosine deaminases ADA1 and ADA2. Decrease in ADAs concentration due to genetic defects in the ADA genes leads to serious perturbation in the immune system function while increase in ADA activity associates with numerous immune diseases and cancers. The immune responses to extracellular adenosine have largely been studied using pharmacological approach where non-hydrolysable adenosine receptors agonists substitute adenosine to form the activated state of adenosine receptors. On contrary, adenosine receptors bound to adenosine receptor antagonists mimic inactivated state of adenosine receptors. Here, the effect of adenosine receptor agonists and antagonists on the monocytes function as well as and T helper cell proliferation and differentiation was compared with the effect of adenosine and adenosine deaminases. It was demonstrated that adenosine deaminases control the immune cells responses to activation signals by reducing the concentration of extracellular adenosine and that the cells sensitivity to adenosine greatly depends on the type of the cell activation. Therefore, our data suggests that ADAs could be considered as new drug candidates for the treatment of immune disorders and cancers.
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Kaplan, G. B., and M. T. Sears. "Adenosine receptor agonists attenuate and adenosine receptor antagonists exacerbate opiate withdrawal signs." Psychopharmacology 123, no. 1 (January 1996): 64–70. http://dx.doi.org/10.1007/bf02246282.
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Zhang, Jinfeng, Wenzhong Yan, Wenwen Duan, Kurt Wüthrich, and Jianjun Cheng. "Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists." Pharmaceuticals 13, no. 9 (September 8, 2020): 237. http://dx.doi.org/10.3390/ph13090237.
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The A2A adenosine receptor (A2AAR) plays critical roles in human physiology and pathophysiology, which makes it an important drug target. Previous drug-discovery efforts targeting the A2AAR have been focused on the use of A2AAR antagonists for the treatment of Parkinson’s disease. More recently, the A2AAR has attracted additional attention for its roles in immuno-oncology, and a number of A2AAR antagonists are currently used as lead compounds for antitumor drugs in both preclinical models and clinical trials. This review surveys recent advances in the development of A2AAR antagonists for cancer immunotherapy. The therapeutic potential of representative A2AAR antagonists is discussed based on both animal efficacy studies and clinical data.
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Koscso, Balazs, Zsolt Selmeczy, Leonora Himer, Balazs Csoka, and Gyorgy Hasko. "Adenosine receptor activation augments IL-10 production by murine microglial cells (116.31)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 116.31. http://dx.doi.org/10.4049/jimmunol.186.supp.116.31.
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Abstract Microglia, the intrinsic macrophages of the central nervous system produce the anti-inflammatory cytokine IL-10 following activation with the bacterial cell wall product peptidoglycan (PGN), which is recognized by Toll-like receptor 2 (TLR2). Adenosine is an endogenous purine nucleoside that binds to specific G protein-coupled receptors (A1, A2A, A2B, and A3), and is a well known modulator of the immune system. In this study we investigated the effect of adenosine on IL-10 production by microglia. Cells were treated with adenosine, or selective adenosine receptor agonists and antagonists, in conjunction with 20 μg/ml PGN for 6 or 24 hours. Adenosine treatment augmented IL-10 production by microglia activated with PGN. The non-selective adenosine receptor agonist NECA was the most potent IL-10 inducer, and its effect was prevented by pretreatment with the A2B antagonist MRS-1754. Adenosine receptor activation augmented IL-10 mRNA levels, and this effect was prevented by blocking transcription with actinomycin D. The stimulatory effect of adenosine on IL-10 production was mediated by p38 because it was reversed with a p38 pathway inhibitor. IL-10 promoter analysis and chromatin immunoprecipitation (CHIP) experiments suggested that CREB activation is necessary for the effect of adenosine. These results demonstrate that A2B adenosine receptor activation augments IL-10 production by PGN-activated microglial cells through a p38- and CREB-mediated pre-transcriptional mechanism.
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Sarkar, Bidisha, Santanu Maiti, Gajanan Raosaheb Jadhav, and Priyankar Paira. "Discovery of benzothiazolylquinoline conjugates as novel human A 3 receptor antagonists: biological evaluations and molecular docking studies." Royal Society Open Science 5, no. 2 (February 2018): 171622. http://dx.doi.org/10.1098/rsos.171622.
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Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A 3 receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the h A 3 receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compounds are rationalized with the molecular docking results. Compound 6a showed best potency and selectivity at h A 3 among other adenosine receptors.
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Tung, Avery, Stacy Herrera, Martin J. Szafran, Kristen Kasza, and Wallace B. Mendelson. "Effect of Sleep Deprivation on Righting Reflex in the Rat Is Partially Reversed by Administration of Adenosine A1 and A2 Receptor Antagonists." Anesthesiology 102, no. 6 (June 1, 2005): 1158–64. http://dx.doi.org/10.1097/00000542-200506000-00015.
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Background Similarities between naturally occurring sleep and general anesthesia suggest that the two states may interact physiologically. The authors have previously demonstrated that sleep deprivation potentiates anesthetic-induced loss of righting reflex (LORR) in rats. One possible mediator for this effect is adenosine, which accumulates in the brains of sleep-deprived animals and reduces anesthetic requirements. The authors tested in rats the hypothesis that potentiating effects of sleep deprivation on LORR can be altered by adenosine A1 and A2a receptor antagonists. Methods Five experiments were conducted. In each, rats underwent four trials, consisting of a 24-h period of either sleep deprivation or ad libitum activity followed by administration of a fixed dose of an adenosine antagonist or vehicle. Rats were then given isoflurane, and the time to LORR and recovery were measured. Each experiment tested a specific dose of an A1 receptor antagonist (8-cyclopentyltheophylline given via microinjection into the basal forebrain), an A2a receptor antagonist (ZM241385 via intraperitoneal administration), or both. In each experiment, all rats received all combinations of activity and drug/vehicle, separated by 5-7 days. Results In rested rats, neither antagonist altered the time to LORR. In sleep-deprived rats, both ZM241385 and 8-cyclopentyltheophylline prolonged the time to LORR and shortened recovery in a dose-dependent manner. Prolongation also occurred when subtherapeutic doses of both agents were coadministered. Conclusion Both antagonists partially reversed the effect of sleep deprivation on anesthetic action. This result implies that deprivation-induced changes in adenosine receptor activity can alter LORR. Neither antagonist completely reversed this effect, suggesting possible non-adenosine-mediated effects of sleep deprivation.