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Journal articles on the topic "Adenosine receptor antagonists"
1
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.
Dissertations / Theses on the topic "Adenosine receptor antagonists"
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Beauglehole, Anthony Robert, and anthony@adenrx com. "N3-substituted xanthines as irreversible adenosine receptor antagonists." Deakin University. School of Biological and Chemical Sciences, 2000. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20080612.084330.
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8-Cyclopentyl-3-(3-(4-fluorosulfonylbenzoyl)oxy)propyl-propylxanthine (44, FSCPX) has been reported to exhibit potent and selective irreversible antagonism of the A1 adenosine receptor when using in vitro biological preparations. However, FSCPX (44) suffers from cleavage of the ester linkage separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine pharmacophore when used in in vivo biological preparations or preparations containing significant enzyme activity, presumably by esterases. Cleavage of the ester linkage renders FSCPX (44) inactive in terms of irreversible receptor binding. In order to obtain an irreversible A1 adenosine receptor antagonist with improved stability, and to further elucidate the effects of linker structure on pharmacological characteristics, several FSCPX (44) analogues incorporating the chemoreactive 4-(fluorosulfonyl)phenyl moiety were targeted, where the labile ester linkage has been replaced by more stable functionalites. In particular, ether, alkyl, amide and ketone linkers were targeted, where the length of the alkyl chain was varied from between one to five atoms.
Synthesis of the target compounds was achieved via direct attachment of the N-3 substituent to the xanthine. These compounds were then tested for their biological activity at the A1 adenosine receptor via their ability to irreversibly antagonise the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX, ( 9) to the A1 adenosine receptor of DDT1 MF-2 cells. For comparison, the xanthines were also tested for their ability to inhibit the binding of [3H]-4-(2-[7-amino-2-{furyl} {1,2,4}- triazolo{2,3-a} {1,3,5}triazin-5-ylamino-ethyl)]phenol ([3H]ZM241385, 36) to the A2A adenosine receptor of PC-12 cells. The results suggest that the length and chemical composition of the linker separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine ring contribute to the potency and efficacy of the irreversible A1 adenosine receptor ligands. Like FSCPX (44, IC50 A1 = 11.8 nM), all derivatives possessed IC50 values in the low nM range under in vitro conditions. Compounds 94 (IC50 A1 = 165 nM), 95 (IC50 A1 = 112 nM) and 96 (IC50 A1 = 101 nM) possessing one, three and five methylene spacers within the linkage respectively, exhibited potent and selective binding to the A1 adenosine receptor versus the A2A adenosine receptor. Compound 94 did not exhibit any irreversible binding at A1 adenosine receptors, while 95 and 96 exhibit only weak irreversible binding at A1 adenosine receptors. Those compounds containing a benzylic carbonyl separating the 4-(fluorosulfonyl)phenyl moiety from the xanthine ring in the form of an amide (119, IC50 A1 = 24.9 nM, and 120, IC50 A1 = 21 nM) or ketone (151, IC50 A1 = 14 nM) proved to be the most potent, with compound 120 exhibiting the highest selectivity of 132-fold for the A receptor over the A2A receptor. compounds 119, 120 and 151 also strongly inhibited the binding of [3H]DPCPX irreversibly (82%, 83% and 78% loss of [3H]DPCPX binding at 100 nM respectively). compounds 120 and 151 are currently being evaluated for use in in vivo studies.
Structure-activity studies suggest that altering the 8-cycloalkyl group of A1 selective xanthines for a 3-substituted or 2,3-disubstituted styryl, combined with N-7 methyl substitution will produce a compound with high affinity and selectivity for the A2A adenosine receptor over the A1 adenosine receptor. Compound 167 (IC50 A2A = 264 nM) possessing 8-(m-chloro)styryl substitution and the reactive 4-(fluorosulfonyl)phenyl moiety separated from the xanthine ring via an amide linker in the 3-position (as for 119 and 120), exhibited relatively potent binding to the A2A adenosine receptor of PC-12 cells, with a 16-fold selectivity for that receptor over the A1 adenosine receptor. However, compound 167 exhibited only very weak irreversible binding at A2A adenosine receptors.
Overall, at this stage of biological testing, compound 120 appears to possess the most advantageous characteristics as an irreversible antagonist for the A1 adenosine receptor. This can be attributed to its high selectivity for the A1 adenosine receptor as compared to the A2A adenosine receptor. It also has relatively high potency for the A1 adenosine receptor, a concentration-dependent and selective inactivation of A1 adenosine receptors, and unbound ligand is easily removed (washed out) from biological membranes. These characteristics mean compound 151 has the potential to be a useful tool for the further study of the structure and function of the A1 adenosine receptor.
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BARALDI, Stefania. "Design and Synthesis of New A2B Adenosine Receptor Antagonists." Doctoral thesis, Università degli studi di Ferrara, 2009. http://hdl.handle.net/11392/2388704.
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Starting from chemical structure of N-benzo-[1,3]dioxol-5-yl-2-[5-(2,6dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol3-yloxy]-acetamide, MRE2029F20* various structural modifications were realized to afford a new series of A2B antagonists.
The bioisosteric replacement of the anilide moiety with benzimidazole or quinazoline rings, the effect of the substitution of pyrazole with isoxazole
moiety were investigated. Amide bond has been also replaced with the 5phenyl-1,2,4-oxadiazole nucleus on the basis of other adenosine pharmacophores reported previously. In this context the effect of the nitrogen at the 9-position has been also studied preparing four 9-deaza direct analogs of 8pyrazol-xanthine compounds to compare affinity and selectivity at A2B adenosine receptor. The most significant result was obtained by bioisosteric replacement of the anilide moiety with benzimidazole, achieving antagonists with high affinity and selectivity toward the A2BAR. In particular compound 8-[5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (hA1 Ki = 2530 nM, hA2A Ki > 1000 nM, hA2B Ki = 9.4 nM, hA3 Ki > 1000 nM) and
compound 8-[5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7 dihydro-purine-2,6-dione (hA1 Ki = 4462 nM, hA2A Ki > 1000 nM, hA2B Ki = 25 nM, hA3 Ki > 1000 nM), showed the best biological data.
These new selective and potent A2B antagonists will aid in the elucidation of the physiological role of this receptor and possibily lead to therapeutilally useful agents for treating asthma, diabetes and other diseases.
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Robinson, Sarel Johannes. "Syntheses of chalcones and 2-aminopyrimidines and their evaluation as monoamine oxidase inhibitors and as adenosine receptor antagonists / Sarel Johannes Robinson." Thesis, North-West University, 2013. http://hdl.handle.net/10394/9534.
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Background and rationale -
Parkinson’s disease is a neurodegenerative disorder characterised by reduced levels of
dopamine in the brain. The cause of Parkinson's disease is still unknown; however several
theories pertaining to the etiology exist. Current treatment mainly aims at dopamine
replacement, with agents such as levodopa and dopamine agonists that provide patients
with symptomatic relief. This relief is unfortunately only temporary as the progression of the
disease is not halted. Furthermore, these therapies are associated with a range of side
effects and novel approaches to the treatment are thus urgently required. Adenosine A2A
receptor antagonists recently emerged as a promising non-dopaminergic alternative, not
only as symptomatic treatment, but also as potential neuroprotective therapy.
Adenosine A2A receptors are co-localised with dopamine D2 receptors in the striatum and
other nuclei of the basal ganglia. Adenosine A2A stimulation decreases the affinity of
dopamine for the D2 receptor, and increase cyclic AMP (cAMP) levels. The stimulation of
dopamine D2 receptors, in contrast, decreases cAMP levels and therefore these receptors
(A2A and D2), act in an opposing manner. Adenosine A2A antagonism will thus have similar
effects as dopamine D2 agonism and will reduce the postsynaptic effects of dopamine
depletion to give symptomatic relief. There are also several mechanisms where by
adenosine A2A antagonists may be neuroprotective, for example by preventing glutamate
excitotoxicity, that may cause damage to dopaminergic neurons. A number of adenosine A2A
antagonists have already reached clinical trials and promising results were obtained,
especially when combined with levodopa. Consequently, A2A antagonists are realistic
prospects that have therapeutic potential in diseases with dopaminergic hypofunction, like
Parkinson's disease. Many of the current A2A antagonists contain an amino-substituted
heterocyclic scaffold, such as an aminopyrimidine. The primary aim of this study was the
design, synthesis and evaluation of 2-aminopyrimidine derivatives as adenosine A2A receptor
antagonists.
Monoamine oxidase B (MAO-B) inhibitors are also promising candidates for the symptomatic
treatment of Parkinson's disease, since MAO-B is the enzyme primarily responsible for the catabolism of dopamine in the brain. Irreversible inhibitors of MAO-B, such as selegeline and
rasagiline, have been used clinically for the treatment of Parkinson's disease. This type of
inhibition comes with certain disadvantages as it may take up to several weeks after
termination of treatment for the enzyme activity to recover. Reversible inhibitors in contrast
will have much better safety profiles seeing that they will not inactivate the enzyme
permanently and allow for competition with the substrate.
When dopamine is oxidized by MAO, toxic metabolic by-products, such as hydrogen
peroxide (H2O2) forms, and this is believed to be a possible cause of Parkinson's disease.
MAO-B inhibitors will therefore not only provide symptomatic relief but may also alter the
progression of the disease by preventing the formation of these byproducts. Promising MAOB
inhibitory activities have been reported for chalcones, and since the intermediates
obtained in the synthesis of aminopyrimidines in this study are chalcones, a secondary aim
of this study was the screening of selected chalcone intermediates as inhibitors of MAO–B.
Results -
Design and synthesis: A series of 2-aminopyrimidines were designed using known active
structures and literature pharmacophores. A molecular modelling study (Discovery Studio
3.1, Accelrys) was further done to investigate the feasibility of these compounds as potential
adenosine A2A antagonists. All of the designed aminopyrimidines were successfully docked
in the binding site of the adenosine A2A receptor. Binding orientations and observed
interactions with important residues in the active site were similar to those observed for
known A2A antagonists. It was therefore concluded that these compounds may be potential
A2A antagonists and the designed compounds were thus synthesised. Structures were
primarily confirmed with nuclear magnetic resonance spectroscopy and mass spectrometry.
MAO-B inhibition studies: Selected chalcones were evaluated using a fluorometric assay
and kynuramine as substrate. The compounds were potent and selective inhibitors of the
MAO-B enzyme with IC50 values ranging between 0.49-7.67 μM. (2E)-3-(3-Chlorophenyl)-1-
(5-methyl-2-furyl)prop-2-en-1-one (1c) was the most potent compound with an IC50 value of
0.49 μM and was approximately 60 times more selective towards MAO-B than MAO-A.
Some preliminary structure activity relationships were derived, for example, phenyl
substitution with an electron withdrawing chlorine group generally resulted in better activity
than substitution with electron donating methoxy groups. Further investigation of structure
activity relationships are however required as a very small series of chalcones were
screened.
Reversibility studies and mode of inhibition: A dilution assay was used to determine whether
compound (1c) binds reversibly or irreversibly to the MAO-B enzyme. This was done by measuring the recovery of enzymatic activity after a large dilution of the enzyme-inhibitor
complex. The results from the reversibility studies showed that the inhibition of the most
potent compound (1c) is reversible as the catalytic activities are recovered to approximately
80% and 50% respectively, compared to the control measured in the absence of an inhibitor.
For the mode of inhibition, sets of Lineweaver–Burk plots were constructed. The Lineweaver-
Burk plots intersected on the y-axis which indicates that compound 1c is a competitive inhibitor
of the MAO-B enzyme.
In vitro adenosine A2A assays: Radioligand binding assays were used to determine the
affinity of the synthesised 2-aminopyrimidines for the adenosine A2A receptor. This assay
was performed with the radioligand [3H]NECA in the presence of N6-cyclopentyladenosine
(CPA). Compounds 2a - 2h showed moderate to weak affinity in the assay, while promising
affinities were observed for compounds 2j - 2n, which all exhibited Ki values below 55 nM.
The compound with the highest affinity was 4-(5-methylfuran-2-yl)-6-[3-(piperidine-1-
carbonyl)phenyl]pyrimidin-2-amine (2m) with a Ki value of 5.76 nM, which is comparable to
the Ki value of 2.10 nM obtained for the known amino-substituted heterocyclic adenosine A2A
antagonist, ZM 241385. The higher affinities of compounds (2j – 2n) could, at least in part,
be explained by the molecular modellling studies. In the docking experiments an additional
hydrogen bond interaction was observed between the amide carbonyl and tyrosine 271
indicating that this structural feature is a major contributing factor to the improved affinity
observed for these derivatives.
In vivo adenosine A2A assays: The haloperidol induced catalepsy assay was used to
determine whether the two compounds with the highest affinity for the adenosine A2A
receptor (2m and 2k) are antagonists of the A2A receptor. These compounds caused a
statistically significant reduction in catalepsy, which clearly illustrate that they are adenosine
A2A antagonists.
The objectives of this study as set out were thus successfully realised and promising results
were obtained. During this study, several novel 2-aminopyrimidines and chalcones were
synthesised, and the respective adenosine A2A antagonistic and monoamine oxidase
inhibitory activities for all of the screened compounds were determined for the first time.Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013
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McKeveney, Declan, and n/a. "The Solid-Phase Combinatorial Synthesis of 2,6,9- Trisubstituted Purines as Potential Adenosine A3 Receptor Antagonists." Griffith University. School of Science, 2005. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050830.120105.
Full textAbstract:
Purines as a class of compounds have been implicated in many biological systems, including as adenosine receptor antagonists. A method of synthesising 2,6,9-trisubstituted purines would be useful to produce small libraries of compounds for probing adenosine receptor selectivity. A library of trisubstituted purines has been achieved using a solid-phase methodology. The electronic properties of the substrate were found to result in difficulties with the loading of substrate onto the resin. Theoretical calculations provided the basis for mono-substitution in order to activate the substrate. This modified substrate has loaded onto the resin in reproducible and high yields. Amine and thiol, on-resin, C-2 substitution was shown to proceed at room temperature. This represents significantly milder conditions than are generally seen in the literature. This is due to the activating effect of the carbamate linker chosen on the pyrimidine ring. This also results in a faster reaction rate than is seen in the corresponding solution-phase reaction. This study showed that the electronic profile of the loaded substrate was responsible for the low alkylation on the carbamate nitrogen of loaded dichloro- or C-6 substituted chloropyrimidines. This reaction was modified by activating the pyrimidine ring via C-2 substitution and has been shown to go to completion with three different alkyl groups to give a clean product direct from resin cleavage. On-resin nitro reduction had been planned. The resin bound product would then be carried on to the next step of resin cleavage and cyclisation of the imidazole ring to give the final purine products. On resin reduction could not be achieved, however, cleavage of the compound from the resin and reduction in solution was found to be efficient as the cyclisation reagents could be included in this step without interfering with yield or purity of products and so this represents a clear improvement upon the planned synthesis. Efforts to fully characterise the library brought up issues of purine NMR. Extremely broad signals were observed in the proton spectra of many of the compounds making assignments difficult. Broad 13C NMR signals have also been observed. Restricted rotation about the substituent N-C bond is responsible for these problems. Crystal structure data has confirmed the double bond character of this bond with one of the substituted pyrimidines. High temperature NMR experiments have demonstrated how this can be overcome and the fine structure of the spectra observed. HMBC and COSY correlations have been used alongside the 1H and 13C spectra to allow full characterisation of the compounds wherever possible. Receptor homology models were created and updated for all four adenosine receptor subtypes. Known adenosine agonists and antagonists were created and minimised for use in docking experiments. Receptor docking experimental data is reported. Binding assays are being carried out by a third party and will be submitted for publication at a later date. A small library of 2,6,9-trisubstituted purines has been synthesised, exemplifying an efficient and robust method to achieve pure compounds for biological evaluation. A good level of diversity has been achieved at each combinatorial position (two substitutions and an N-alkylation). Final compounds have been isolated in good yields with a high level of purity.
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McKeveney, Declan. "The Solid-Phase Combinatorial Synthesis of 2,6,9- Trisubstituted Purines as Potential Adenosine A3 Receptor Antagonists." Thesis, Griffith University, 2005. http://hdl.handle.net/10072/367926.
Full textAbstract:
Purines as a class of compounds have been implicated in many biological systems, including as adenosine receptor antagonists. A method of synthesising 2,6,9-trisubstituted purines would be useful to produce small libraries of compounds for probing adenosine receptor selectivity. A library of trisubstituted purines has been achieved using a solid-phase methodology. The electronic properties of the substrate were found to result in difficulties with the loading of substrate onto the resin. Theoretical calculations provided the basis for mono-substitution in order to activate the substrate. This modified substrate has loaded onto the resin in reproducible and high yields. Amine and thiol, on-resin, C-2 substitution was shown to proceed at room temperature. This represents significantly milder conditions than are generally seen in the literature. This is due to the activating effect of the carbamate linker chosen on the pyrimidine ring. This also results in a faster reaction rate than is seen in the corresponding solution-phase reaction. This study showed that the electronic profile of the loaded substrate was responsible for the low alkylation on the carbamate nitrogen of loaded dichloro- or C-6 substituted chloropyrimidines. This reaction was modified by activating the pyrimidine ring via C-2 substitution and has been shown to go to completion with three different alkyl groups to give a clean product direct from resin cleavage. On-resin nitro reduction had been planned. The resin bound product would then be carried on to the next step of resin cleavage and cyclisation of the imidazole ring to give the final purine products. On resin reduction could not be achieved, however, cleavage of the compound from the resin and reduction in solution was found to be efficient as the cyclisation reagents could be included in this step without interfering with yield or purity of products and so this represents a clear improvement upon the planned synthesis. Efforts to fully characterise the library brought up issues of purine NMR. Extremely broad signals were observed in the proton spectra of many of the compounds making assignments difficult. Broad 13C NMR signals have also been observed. Restricted rotation about the substituent N-C bond is responsible for these problems. Crystal structure data has confirmed the double bond character of this bond with one of the substituted pyrimidines. High temperature NMR experiments have demonstrated how this can be overcome and the fine structure of the spectra observed. HMBC and COSY correlations have been used alongside the 1H and 13C spectra to allow full characterisation of the compounds wherever possible. Receptor homology models were created and updated for all four adenosine receptor subtypes. Known adenosine agonists and antagonists were created and minimised for use in docking experiments. Receptor docking experimental data is reported. Binding assays are being carried out by a third party and will be submitted for publication at a later date. A small library of 2,6,9-trisubstituted purines has been synthesised, exemplifying an efficient and robust method to achieve pure compounds for biological evaluation. A good level of diversity has been achieved at each combinatorial position (two substitutions and an N-alkylation). Final compounds have been isolated in good yields with a high level of purity.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Science
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Morizzo, Erika. "G Protein-Coupled Receptors as Potential Drug Target: From Receptor Topology to Rational Drug Design, an in-silico Approach." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3426081.
Full textAbstract:
G protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes, ranging from the transmission of the light and odorant signals to the mediation of neurotransmission and hormonal actions. GPCRs are dysfunctional or deregulated in several human diseases and are estimated to be the target of more than 40% of drugs used in clinical medicine today.
The crystal structures of rhodopsin and the recent published crystal structures of beta-adrenergic receptors and human A2A Adrenergic Receptor provide the information of the three-dimensional structure of GPCRs, which supports homology modeling studies and structure-based drug-design approaches. Rhodopsin-based homology modeling has represented for many years a widely used approach to built GPCR three-dimensional models. Structural models can be used to describe the interatomic interactions between ligand and receptor and how the binding information is transmitted through the receptor.
Both agonist and antagonist like states can be described by several different conformational receptor states depending on the nature of both ligand and receptor. Considering different complementarities, we might explore different conformations of the same pharmacological state.
We investigated the molecular pharmacology of adenosine receptors and, in particular, the human A3 adenosine receptor (hA3AR) by using an interdisciplinary approach to speed up the discovery and structural refinement of new potent and selective hA3AR antagonists. Human A3AR belongs to adenosine receptors family of GPCRs, which consists of four distinct subtypes: A1, A2A, A2B, A3 that are ubiquitously expressed in the human body.
The hA3AR, which is the most recently identified adenosine receptor, is implicated in a variety of important physiological processes. Activation of A3ARs increases the release of inflammatory mediators, such as histamine from rodent mast cells, and it inhibits the production of tumor necrosis factor-alpha. The activation of the hA3AR seems to be involved in immunosuppression and in the response to ischemia of the brain and heart. Agonists or antagonists of A3ARs are potential therapeutic agents for the treatment of ischemic and inflammatory diseases.
The first model of human A3AR has been built using a conventional rhodopsin-based homology modeling approach. The model has been used to probe atomic level specific interactions, detected using site-directed mutagenesis analysis.
The rhodopsin-based model of the hA3AR in its resting state (antagonist-like state) has been revisited, taking into account a novel strategy to simulate the possible receptor reorganization induce by the antagonist-binding. We called this new strategy ligand-based homology modeling (LBHM). It is an evolution of a conventional homology modeling algorithm: any selected atoms will be included in energy tests and in minimization stages of the modeling procedure. Ligand-based option is very useful when one wishes to build a homology model in the presence of a ligand docked to the primary template. Starting from the conventional rhodopsin-based homology model and applying our ligand-based homology modeling implementation we can generate other antagonist-like conformational states of hA3AR in which the ligand recognition cavity is expanded. Using different antagonist-like conformational states, we are able to rationalize the observed activities for all the compounds analyzed. Many severe analysis concerning false-positives and false-negatives situations are usually conducted.
To strictly validate this methodology as novel tool to address the multi-conformational space of GPCRs, we have analyzed different classes of known human A3 antagonists in the corresponding putative ligand binding site: for example triazoloquinoxalin-1-one derivatives, arylpyrazolo-quinoline derivatives and pyrazolo-triazolo-pyrimidines derivatives. These studies led to the identification of groups for every class of antagonists that, introduced one by one in a suitable position, afford high hA3AR affinity and good selectivity.
Starting from these binding requirements, we decided to perform an in silico molecular simplification approach to identify a suitable fragmentation route of the 4-amino-triazoloquinoxalin-1-one scaffold and explore which of the structural features were essential to guarantee efficient ligand-receptor recognition.
With the availability of new three dimensional templates different from rhodopsin, we built new models of hA3AR. All the models were used for a molecular dynamic simulation in a POPC bilayer to investigate the topological fluctuation of the binding pocket.I recettori accoppiati alle proteine G (GPCR) costituiscono una grande famiglia di proteine integrali di membrana caratterizzate da sette eliche transmenmbrana, che mediano un'ampia gamma di processi fisiologici che vanno dalla trasmissione della luce e dei segnali olfattivi alla mediazione della neurotrasmissione e dell'azione degli ormoni. I GPCR mancano di una corretta regolazione in molte patologie umane ed è stato stimato che costituiscano il target del 40% dei medicinali utilizzati attualmente in clinica. La struttura cristallografica della rodopsina e le strutture più recenti del recettore beta adrenergico e del recettore adenosinico A2A forniscono l'informazione strutturale che sta alla base della costruzione di modelli per omologia e degli approcci di structure-based drug design dei GPCR. La costruzione di modelli di GPCR per omologia basati sulla struttura della rodopsina ha rappresentato per molti anni un approccio ampiamente utilizzato. Questi modelli possono essere usati per descrivere le interazioni interatomiche tra ligando e recettore e come le informazioni sono trasmesse attraverso il recettore. Diversi stati conformazionali del recettore possono essere in grado di descrivere la conformazione del recettore che lega l'agonista e quella che lega l'antagonista, a seconda della natura di ligando e recettore. Se si considerano diverse complementarietà, si possono esplorare diversi stati conformazionali di uno stesso stato farmacologico. Noi abbiamo studiato la farmacologia molecolare dei recettori adenosinici e, in particolare, del recettore adenosinico A3 umano (hA3AR), utilizzando un approccio interdisciplinare al fine di massimizzare la scoperta e l'ottimizzazione strutturale di nuovi antagonisti potenti e selettivi per il hA3AR. Il hA3AR fa parte della famiglia dei recettori adenosinici che consiste in quattro diversi sottotipi (A1, A2A, A2B, A3) che sono espressi in tutto il corpo umano. Il recettore adenosinico A3 è stato identificato più recentemente ed è implicato in importanti processi fisologici. L'attivazione del hA3AR aumenta il rilascio di mediatori dell'infiammazione, come l'istamina dalle mastcellule, e inibisce la produzione del TNF-alpha. L'attivazione del hA3AR sembra essere coinvolta nell'immunosoppressione e nella risposta ischemica di cuore e cervello. Agonisti o antagonisti del hA3AR sono potenziali agenti terapeutici nel trattamento di patologie ischemiche e infiammatorie. Il primo modello di hA3AR è stato costruito usando un approccio convenzionale di homology modeling basato sulla rodopsina ed è nel suo stato che lega l'antagonista. Dopo essere stato utilizzato per verificare le interazioni a livello molecolare che erano state evidenziate da studi di mutagenesi, il modello è stato rivisto prendendo in considerazione una nuova strategia che simula la possibile riorganizzazione del recettore indotta dal legame con l'antagonista. Abbiamo chiamato questa strategia ligand-based homology modeling. E' un'evoluzione dell'algoritmo convenzionale di homology modeling: ogni atomo selezionato viente preso in considerazione nei test energetici e nelle fasi di minimizzazione della procedura di modeling. L'opzione ligand-based è molto utile quando si vuole costruire un modello per omologia in presenza di un ligando nella sua ipotetica conformazione di legame nel templato iniziale. A partire dal modello ottenuto dalla rodopsina e applicando la tecnica del LBHM, possiamo generare altri stati conformazionali del recettore hA3AR che legano l'antagonista, nei quali la cavità di riconoscimento del ligando è espansa. Usando diversi stati conformazionali che legano l'antagonista, possiamo razionalizzare l'attività misurata sperimentalmente di tutti i composti analizzati. Sono condotte severe analisi relative a falsi positivi e falsi negativi. Per validare la metodologia come nuovo strumento per indirizzare lo spazio multiconformazionale dei GPCR, abbiamo analizzato diverse classi di antagonisti con attività nota sul hA3AR: ad esempio derivati triazolo-chinossalinonici, derivati arilpirazolo-chinolinici e derivati pirazolo-triazolo-pirimidinici. Questi studi hanno portato all'identificazione di gruppi per ogni classe di antagonisti che, se introdotti in una precisa posizione, portano ad un'alta affinità e ad una buona selettività per il hA3AR. A partire dalle caratteristiche risultate importanti per il legame, abbiamo applicato una tecnica di semplificazione molecolare in silico per identificare una possibile via di frammentazione della struttura 4-amino-triazolochinoassalin-1-onica ed esplorare quali sono le caratteristiche strutturali essenziali per garantire un'efficiente riconoscimento ligando-recettore. Con la disponibilità di nuove strutture tridimensionali da utilizzare come templati diversi dalla rodopsina, abbiamo costruito nuovi modelli del recettore hA3AR. Tutti i modelli sono stati usati per una simulazione di dinamica molecolare in un doppio strato fosfolipidico, per analizzare le fluttuazioni topologiche della tasca di legame.
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Affini, Anna [Verfasser]. "Histamine H3 receptor antagonists in combination with monoamine oxidase B and adenosine A1/A2A receptor ligands as multi-target approach for the treatment of Parkinson´s disease / Anna Affini." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2019. http://d-nb.info/1190350807/34.
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Harmse, Rozanne. "Syntheses of 8-(phenoxymethyl)caffeine analogues and their evaluation as inhibitors of monoamine oxidase and as antagonists of the adenosine A2A receptor / Rozanne Harmse." Thesis, North-West University, 2013. http://hdl.handle.net/10394/9663.
Full textAbstract:
Background and rationale: Parkinson’s disease (PD) is a progressive, degenerative disorder of the central nervous system and is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The loss of functional dopamine in the striatum is thought to be responsible for the typical symptoms of PD. Cardinal features of PD include bradykinesia, muscular rigidity, resting tremor and impairment of postural balance. This study focuses on the inhibition of monoamine oxidase B (MAO-B) and antagonism of A2A receptors as therapeutic strategies for PD.
Monoamine oxidase (MAO) is a flavin adenine dinucleotide (FAD)-containing mitochondrial bound isoenzyme which consists of two isoforms namely MAO-A and MAO-B. The primary function of MAO is to catalyze the oxidative deamination of dietary amines, monoamine neurotransmitters and hormones. MAO-A is responsible for the oxidative deamination of serotonin (5-HT) and norepinephrine (NE), while MAO-B is responsible for the oxidative deamination of dopamine (DA). The formation of DA takes place in the presynaptic neuron where it is stored in vesicles and released into the presynaptic cleft. The released DA then either binds to D1 and D2 receptors which results in an effector response. The excess DA in the presynaptic cleft is metabolized by MAO-B which may result in the formation of free radicals and a decrease in DA concentrations. Under normal physiological conditions free radicals are removed from the body via normal physiological processes, but in PD these normal physiological processes are thought to be unable to remove the radicals and this may lead to oxidative stress. Oxidative stress is believed to be one of the leading causes of neurodegeneration in PD. The rationale for the use of MAO-B inhibitors in PD would be to increase the natural DA levels in the brain and also diminish the likelihood of free radicals to be formed.
Adenosine is an endogenous purine nucleoside and yields a variety of physiological effects. Four adenosine receptor subtypes have been characterized: A1, A2A, A2B and A3. They are all part of the G-protein-coupled receptor family and have seven transmembrane domains. The A2A receptor is highly concentrated in the striatum. There are two important pathways in the basal ganglia (BG) through which striatal information reaches the globus pallidus, namely the direct pathway containing A1 and D1 receptors and the indirect pathway containing A2A and D2 receptors. The direct pathway facilitates willed movement and the indirect pathway inhibits willed movement. A balance of the two pathways is necessary for normal movement. In PD, there is a decrease in DA in the striatum, thus leading to unopposed A2A receptor signaling and ultimately resulting in overactivity of the indirect pathway. Overactivity of the indirect pathway results in the locomotor symptoms associated with PD. Treatment with an A2A antagonist will block the A2A receptor, resulting in the restoration of balance between the indirect and direct pathways, thus leading to a decrease in locomotor symptoms.
Aim: In this study, caffeine served as a lead compound for the design of dual-targeted drugs that are selective, reversible MAO-B inhibitors as well as A2A antagonists. Caffeine is a very weak MAO-B inhibitor and a moderately potent A2A antagonist. Substitution on the C8 position of caffeine yields compounds with good MAO-B inhibition activities and A2A receptor affinities. An example of this behaviour is found with (E)-8-(3-chlorostyryl)caffeine (CSC), which is not only a potent A2A antagonist but also a potent MAO-B inhibitor. The goal of this study was to identify and synthesize dual-targeted xanthine compounds. Recently Swanepoel and co-workers (2012) found that 8-phenoxymethyl substituted caffeines are potent reversible inhibitors of MAO-B. Therefore, this study focused on expanding the 8-(phenoxymethyl)caffeine series and evaluating the resulting compounds as both MAO-A and -B inhibitors as well as A2A antagonists.
Synthesis: Two series were synthesized namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines. The analogues were synthesized according to the literature procedure. 1,3-Dimethyl-5,6-diaminouracil or 1,3-diethyl-5,6-diaminouracil were used as starting materials and were acylated with a suitable substituted phenoxyacetic acid in the presence of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC) as an activating reagent. The intermediary amide was treated with sodium hydroxide, which resulted in ring closure to yield the corresponding 1,3-dimethyl-8-phenoxymethyl-7Hxanthinyl or 1,3-diethyl-8-phenoxymethyl-7H-xanthinyl analogues. These xanthines were 7-N-methylated in the presence of an excess of potassium carbonate and iodomethane to yield the target compounds.
In vitro evaluation: A radioligand binding assay was performed to determine the affinities of the synthesized compounds for the A2A receptor. The MAO-B inhibition studies were carried out via a fluorometric assay where the MAO-catalyzed formation of H2O2 was measured.
Results: Both series showed good to moderate MAO-B inhibition activities, while none of the compounds had activity towards MAO-A. Results were comparable to that of a known MAOB inhibitor lazabemide. For example, lazabemide (IC50 = 0.091 μM) was twice as potent as the most potent compound identified in this study, 8-(3-chlorophenoxymethyl)caffeine (compound 3; IC50 = 0.189 μM). Two additional compounds, 8-(4-iodophenoxymethyl)caffeine and 8-(3,4-dimethylphenoxymethyl) caffeine, also exhibited submicromolar IC50 values for the inhibition of MAO-B. The structure-activity relationships (SARs) indicated that 1,3-diethyl substitution resulted in decreased inhibition potency towards MAO-B and that 1,3-dimethyl substitution was a more suitable substitution pattern, leading to better inhibition potencies towards MAO-B.
The compounds were also evaluated for A2A binding affinity, and relatively weak affinities were recorded with the most potent compound, 1,3-diethyl-7-methyl-8-[4-chlorophenoxymethyl]xanthine (compound 16), exhibiting a Ki value of 0.923 μM. Compared to KW-6002 (Ki = 7.94 nM), a potent reference A2A antagonist, compound 16 was 35-fold less potent. Comparing compound 16 to CSC [Ki(A2A) = 22.6 nM; IC50(MAO-B) = 0.146 nM], it was found that compound 16 is 31-fold less potent as an A2A antagonist and 21-fold less potent as a MAO-B inhibitor. Loss of MAO-B inhibition potency may be attributed to 1,3-diethyl substitution which correlates with similar conclusions reached in earlier studies. In addition, the replacement of the styryl functional group (as found with CSC and KW-6002) with the phenoxymethyl functional group (as found with the present series) may explain the general reduction in affinity for the A2A receptor. This suggests that the styryl side chain is more appropriate for A2A antagonism than the phenoxymethyl functional group.
Conclusion: In this study two series of xanthine derivatives were successfully synthesized, namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines (11 compounds in total). Three of the newly synthesized compounds were found to act as potent inhibitors of MAO-B, with IC50 values in the submicromolar range. None of the compounds were however noteworthy MAO-A inhibitors. The most potent A2A antagonist among the examined compounds, compound 16, proved to be moderately potent compared to the reference antagonists, CSC and KW-6002. It may be concluded that the styryl functional group (as found with CSC and KW-6002) is more optimal than the phenoxymethyl functional group (as found with the present series) for A2A antagonism. 1,3-Diethyl substitution of the xanthine ring was found to be less optimal for MAO-B inhibition compared to 1,3-dimethyl substitution. These results together with known SARs provide valuable insight into the design of 8-(phenoxymethyl)caffeines as selective and potent MAO-B inhibitors. Such drugs may find application in the therapy of PD.Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.
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Pretorius, Judey. "The synthesis and evaluation of caffeine analogues as inhibitors of monoamine oxidase B and antagonists of the adenosine A₂A receptor / by Judey Pretorius." Thesis, North-West University, 2008. http://hdl.handle.net/10394/4127.
Full textAbstract:
The adenosine A2A receptor has emerged as an attractive target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonists of the A2A receptor (A2A antagonists) partially alleviate the symptoms of PD, prevent the development of motor complications and may also slow the underlying neurodegenerative process. It was recently reported that several members of the (E)-8-styrylcaffeine class of A2A antagonists also are potent inhibitors of monoamine oxidase B (MAO-B).Thesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2009.
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Gull, Mazhar [Verfasser], and André [Akademischer Betreuer] Brändli. "In vivo pharmacological profiling in Xenopus embryos defines a subset of A1 adenosine receptor-selective antagonists with potent anti-angiogenic activities / Mazhar Gull ; Betreuer: André Brändli." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1137226765/34.
Full textBooks on the topic "Adenosine receptor antagonists"
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Hiroshi, Kase, Richardson Peter J, and Jenner P. G, eds. Adenosine receptors and Parkinson's disease. San Diego, Calif: Academic, 2000.
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Hiroshi, Kase, Richardson Peter J, and Jenner Peter 1946-, eds. Adenosine receptors and Parkinson's disease. San Diego, CA: Academic Press, 2000.
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service), SpringerLink (Online, ed. Adenosine receptors in health and disease. Dordrecht: Springer, 2009.
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1953-, Jacobson Kenneth Alan, and Jarvis Michael F, eds. Purinergic approaches in experimental therapeutics. New York: Wiley-Liss, 1997.
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Chen, Jiang-Fan, and Akihisa Mori. Adenosine A2A Receptor Antagonists. Elsevier Science & Technology Books, 2023.
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Jenner, Peter, Hiroshi Kase, and Peter J. Richardson. Adenosine Receptors and Parkinson's Disease. Elsevier Science & Technology Books, 1999.
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Wilson, Constance N., and S. Jamal Mustafa. Adenosine Receptors in Health and Disease. Springer, 2016.
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(Editor), Hiroshi Kase, Peter J. Richardson (Editor), and Peter Jenner (Editor), eds. Adenosine Receptors and Parkinson's Disease (Pure and Applied Mathematics (Academic Press), 60.). Academic Press, 2000.
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Beninger, Richard J. Dopamine receptor subtypes and incentive learning. Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780198824091.003.0007.
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Dopamine receptor subtypes and incentive learning explains that dopamine receptors are G protein-coupled and form two families: D1-like receptors, including D1 and D5, stimulate adenylyl cyclase and cyclic adenosine monophosphate (cAMP); D2-like receptors, including D2, D3, and D4, inhibit cAMP. Antipsychotic medications are dopamine receptor antagonists and their clinical potency is strongly correlated with blockade of D2 receptors, implicating overactivity of D2 receptors in psychosis in schizophrenia. D1- and D2-like receptors appear to be involved in unconditioned locomotor activity and incentive learning. D1-like receptors are implicated more strongly in incentive learning and D2-like receptors more strongly in locomotion. D3 receptors may play a relatively greater role in expression than acquisition of incentive learning. Dopamine receptor subtypes form heteromers with each other and with the receptors of other neurotransmitters (e.g., glutamate, adenosine, ghrelin) and the signaling properties of these heteromers can differ from those of either receptor in isolation.
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Erlinge, David, and Göran Olivecrona. Diagnosis and management of ST-elevation of myocardial infarction. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0147.
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ST-elevation myocardial infarction (STEMI) is generally caused by a ruptured plaque that triggers local thrombus formation, which occludes the coronary artery. STEMI should be diagnosed rapidly, based on the combination of ST-segment elevation and symptoms of acute myocardial infarction. The main treatment objective is myocardial tissue reperfusion as quickly as possible. The preferred method of reperfusion is primary percutaneous coronary interventionif transport time is below 2 hours, and thrombolysis if longer STEMI patients with acute onset cardiogenic shock should be evaluated by echocardiography to exclude mechanical complications, such as flail mitral insufficiency, ventricular septal defect or tamponade. Secondary prevention includes aspirin, adenosine diphosphate receptor antagonists, statins, beta-blockers, angiotensin-converting enzymeinhibitors, and lifestyle changes.
Book chapters on the topic "Adenosine receptor antagonists"
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Shook, Brian C. "Adenosine A2A Receptor Antagonists." In Topics in Medicinal Chemistry, 1–42. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/7355_2014_67.
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Gao, Zhan-Guo, Dilip K. Tosh, Shanu Jain, Jinha Yu, Rama R. Suresh, and Kenneth A. Jacobson. "A1 Adenosine Receptor Agonists, Antagonists, and Allosteric Modulators." In The Adenosine Receptors, 59–89. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-90808-3_4.
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Müller, Christa E., and Kenneth A. Jacobson. "Xanthines as Adenosine Receptor Antagonists." In Methylxanthines, 151–99. Berlin, Heidelberg: Springer Berlin Heidelberg, 2010. http://dx.doi.org/10.1007/978-3-642-13443-2_6.
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Pinna, Annalisa, Nicola Simola, Lucia Frau, and Micaela Morelli. "Symptomatic and Neuroprotective Effects of A2A Receptor Antagonists in Parkinson’s Disease." In Adenosine, 361–84. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4614-3903-5_18.
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Müller, Christa E. "Adenosine A2A Receptor Antagonists in Drug Development." In Current Topics in Neurotoxicity, 39–56. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-20273-0_3.
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Ongini, Ennio, Cristina Zocchi, Anna Conti, Monica Viziano, Angela Monopoli, and Silvio Dionisotti. "Biologic Activity of Adenosine A2a Receptor Antagonists." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 241–48. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_28.
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Kiesman, William F., Elfatih Elzein, and Jeff Zablocki. "A1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers." In Adenosine Receptors in Health and Disease, 25–58. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-89615-9_2.
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Jacobson, Kenneth A., Athena M. Klutz, Dilip K. Tosh, Andrei A. Ivanov, Delia Preti, and Pier Giovanni Baraldi. "Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering." In Adenosine Receptors in Health and Disease, 123–59. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-89615-9_5.
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Baraldi, Pier Giovanni, Romeo Romagnoli, Giulia Saponaro, Stefania Baraldi, Mojgan Aghazadeh Tabrizi, and Delia Preti. "A3 Adenosine Receptor Antagonists: History and Future Perspectives." In A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics, 121–47. Dordrecht: Springer Netherlands, 2009. http://dx.doi.org/10.1007/978-90-481-3144-0_7.
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Costa, Giulia, and Micaela Morelli. "Adenosine A2A Receptor Antagonists in L-DOPA-Induced Motor Fluctuations." In Current Topics in Neurotoxicity, 163–82. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-20273-0_9.
Full textConference papers on the topic "Adenosine receptor antagonists"
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Calzetta, Luigi, Maria G. Matera, Clive Page, Mario Cazzola, and Domenico Spina. "Effects Of Adenosine Receptor Agonist And Antagonists On Human Isolated Bronchi." In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2129.
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Lee, Kyungik, Seungah Jun, EunYoung Byun, Hosun Lee, Yongtaek Lee, MiJin Moon, Yu-Yon Kim, et al. "Abstract 4140: Discovery and characterization of novel highly potent A2A adenosine receptor antagonists for cancerimmunotherapy." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4140.
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Lee, Kyungik, Seungah Jun, EunYoung Byun, Hosun Lee, Yongtaek Lee, MiJin Moon, Yu-Yon Kim, et al. "Abstract 4140: Discovery and characterization of novel highly potent A2A adenosine receptor antagonists for cancerimmunotherapy." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4140.
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Corsello, Steven M., Ryan D. Spangler, Ranad Humeidi, Caitlin N. Harrington, Rohith T. Nagari, Ritu Singh, Vickie Wang, et al. "Abstract 3400: Adenosine receptor antagonists exhibit potent and selective off-target killing of FOXA1-high cancers." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-3400.
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Van Calenbergh, Serge, Andreas Link, Shelly Fujikawa, Veerle Vanheusden, Denis De Keukeleire, Adriaan P. Ijzerman, and Piet Herdewijn. "5'-Deoxy congeners of 9-(3-amido-3-deoxy-β-D-xylofuranosyl)-N6-cyclopentyladenine: New adenosine A1 receptor antagonists." In XIth Symposium on Chemistry of Nucleic Acid Components. Prague: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 1999. http://dx.doi.org/10.1135/css199902273.
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Borges, Fernanda, Maykel Cruz-Monteagudo, Aliuska Morales-Helguera, Yunierkis Pérez-Castillo, M. Natália D. S. Cordeiro, Eduardo Tejera, Cesar Paz-y-Miño, et al. "Virtual screening tailored ensembles of QSAR models for the discovery of dual A2A Adenosine Receptor Antagonists / Monoamine Oxidase B Inhibitors." In MOL2NET, International Conference on Multidisciplinary Sciences. Basel, Switzerland: MDPI, 2015. http://dx.doi.org/10.3390/mol2net-1-b033.
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TEIXEIRA, GUILHERME PEGAS, and ROBSON XAVIER FARIA. "INIBIÇÃO DO RECEPTOR PURINÉRGICO P2X7 COMO UMA NOVA ESTRATÉGIA CONTRA DIABETES TIPO 2." In I Congresso Brasileiro de Doenças Crônicas On-line. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/cronics/7456.
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Introdução: A sinalização purinérgica é um sistema de receptores de membrana ativados por purinas, envolvidos em diversos processos fisiológicos e patológicos do organismo. O receptor purinérgico P2X7 é o mais marcante neste sistema. Trata-se de um receptor ionotrópico ativado por adenosina trifosfato (ATP) extracelular com ampla participação na resposta imunológica e na liberação das citocinas pró-inflamatórias IL-1 e IL-18. A superprodução destes mediadores induz resistência à insulina no tecido adiposo e muscular esquelético através da diminuição do transportador de glicose dependente de insulina GLUT 4, fator este que pode levar ao surgimento da diabetes tipo 2. Objetivo: Apresentar a influência do receptor P2X7 como nova estratégia farmacológica na diabetes tipo 2. Metodologia: Foram selecionados seis trabalhos publicados na literatura dos últimos dez anos. As palavras-chave: receptor P2X7, inflamação, resistência à insulina e diabetes tipo 2 foram usadas em diferentes combinações para a seleção dos artigos. Resultados: Durante a diabetes tipo 2, ácidos graxos livres (AGLs) em excesso levam a complicações no metabolismo da glicose. Os AGLs induzem a transcrição das formas imaturas de IL-1 e IL-18 por meio da sinalização via receptor Toll Like 4. Com o aumento de ATP extracelular, o P2X7 é ativado, promovendo o processo inflamatório através da maturação e liberação das citocinas IL-1 e IL-18 pela sinalização Nod Like Receptor protein 3. Estes mediadores desregulam a fosforilação do substrato do receptor de insulina IRS, diminuindo a translocação de GLUT 4 a membrana plasmática, desta forma aumentando a glicemia sanguínea. Estudos em camundongos C57BL/6 mostraalterações nos parâmetros cardíacos induzidos pela alta concentração de glicose, levando a processos de remodelação cardíaca e estresse oxidativo. Interessantemente, estes quadros foram melhorados com a inibição farmacológica do receptor P2X7. Neste contexto, antagonistas do receptor P2X7 foram utilizados em ensaios clínicos, como as moléculas AZD9056 e CE-224,535 para doenças inflamatórias, mostrando boa tolerabilidade. Desta forma, estes são exemplos de antagonistas que podem ser utilizados em estudos de desordens metabólicas. Conclusão: O receptor P2X7 induz o processo inflamatório na diabetes levando a desregulação da sinalização da insulina. Estratégias utilizando antagonistas deste receptor podem ser promissoras no tratamento da diabetes tipo 2.
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Wachtfogel, Yanina T., Yizhar Floman, Meir Liebergall, Robert W. Colman, and Amiram Eldor. "PLATELET ALPHA2-ADRENERGIC RECEPTOR ABNORMALITIES IN PATIENTS WITH IDIOPATHK: SCOLIOSIS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644567.
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Idiopathic scoliosis is a genetic multisystem disease involving skeletal, biochemical, central nervous svstem, muscle and blood platelet abnormalities. Platelets of patients with idiopathic scoliosis have been shown to have decreased adenosine diphosphate and epinephrine-induced aggregation. Similarities between the contractile protein system of platelets and muscle have made the platelet a popular model for certain aspects of muscle physiology. This study confirmed that 64% of the patient platelets tested exhibited a significantly decreased sensitivity to aggregation bv epinephrine. In seven of the eleven patients studied, epinephrine induced aggregation was markedly decreased, i.e., the threshold of agonist was markedly elevated ≥11 uM). The geometric mean concentration of epinephrine required to produce complete second-wave aggregation in idiopathic scoliosis patients was 8μM. as compared to a control concentration of luM. We therefore examined the platelet alpha2-adrenergic receptors of 17 patients with idiopathic scoliosis bv measuring ligand binding using the selective antagonist, methyl yohimbine. Platelets from healthv individuals had 185 ± 16 sites per platelet with a Kd of 1.90 ± 0.32 nM, while patients with idiopathic scoliosis had 54 ± 22 sites per platelet with a of 1.02 ± 0.03 nM. The number of binding sites per platelet in idiopathic scoliosis patients were significantly decreased (p < 0.05) as compared to controls , while the was not significantly different (p > 0.05) between the two groups. Seven of these patients exhibited a significant decrease (p < 0.05) in the number of alpha2-adrenergic receptors on their platelets while the binding in 7 additional patients was undetectable.Three patients exhibited normal receptor number and affinity as compared to normal individuals. This study indicates a profound alteration in the number and function of the alpha2-adrenergic receptors in platelets of patients with idiopathic scoliosis and indicates the functional heterogeneity of the receptor disorder. Further investigation of platelet abnormalities may give insight into the putative muscle defects.
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DiRenzo, Daniel, Dana Piovesan, Joanne Tan, Dillon H. Miles, Manmohan R. Leleti, Timothy Park, Ferdie Soriano, et al. "Abstract A162: AB928, a dual antagonist of the A2aR and A2bR adenosine receptors, relieves adenosine-mediated immune suppression." In Abstracts: Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 30 - October 3, 2018; New York, NY. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/2326-6074.cricimteatiaacr18-a162.
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Houthuys, Erica, Margreet Brouwer, Florence Nyawouame, Romain Pirson, Reece Marillier, Theo Deregnaucourt, Joao Marchante, et al. "Abstract 1683: A novel adenosine A2A receptor antagonist optimized for high potency in adenosine-rich tumor microenvironment boosts antitumor immunity." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1683.
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