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Adenosine Derivative

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Christa E. Müller – One of the best experts on this subject based on the ideXlab platform.

  • BAY60-6583 Acts as a Partial Agonist at Adenosine A2B Receptors
    The Journal of pharmacology and experimental therapeutics, 2014
    Co-Authors: Sonja Hinz, Svenja K. Lacher, Benjamin F. Seibt, Christa E. Müller
    Abstract:

    BAY60-6583 [2-({6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-yl}sulfanyl)acetamide] is the most potent and selective Adenosine A2B receptor (A2B AR) agonist known to date. Therefore, it has been widely used for in vitro and in vivo experiments. In the present study, we investigated the binding and functional properties of BAY60-6583 in various native and recombinant cell lines with different A2B AR expression levels. In cAMP accumulation and calcium mobimobilization assays, BAY60-6583 was found to be significantly less efficacious than Adenosine or the Adenosine Derivative NECA. When it was tested in human embryonic kidney (HEK)293 cells, its efficacy correlated with the A2B expression level of the cells. In Jurkat T cells, BAY60-6583 antagonized the agonistic effect of NECA and Adenosine as determined in cAMP accumulation assays. On the basis of these results, we conclude that BAY60-6583 acts as a partial agonagonist at Adenosine A2B receptors. At high levels of the physiologic agonist Adenosine, BAY60-6583 may act as an antagonist and block the effects of Adenosine at A2B receptors. This has to be considered when applying the A2B-selective “agonist” BAY60-6583 in pharmacological studies, and previous research results may have to be reinterpreted.

  • Synthesis of BODIPY Derivatives Substituted with Various Bioconjugatable Linker Groups: A Construction Kit for Fluorescent Labeling of Receptor Ligands
    Journal of Fluorescence, 2014
    Co-Authors: Fabian Heisig, Sabrina Gollos, Sven J. Freudenthal, Ali El-tayeb, Jamshed Iqbal, Christa E. Müller
    Abstract:

    The goal of the present study was to design small, functionalized green-emitting BODIPY dyes, which can readily be coupled to target molecules such as receptor ligands, or even be integrated into their pharmacophores. A simple two-step one-pot procedure starting from 2,4-dimethylpyrrole and ω-bromoalkylcarboxylic acid chlorides was used to obtain new ω-bromoalkyl-substituted BODIPY fluorophores ( 1a – 1f ) connected via alkyl spacers of different length to the 8-position of the fluorescent dye. The addition of radical inhibitors reduced the amount of side products. The ω-bromoalkyl-substituted BODIPYs were further converted to introduce various functional groups: iodo-substituted dyes were obtained by Finkelstein reaction in excellent yields; microwave-assisted reaction with methanolic ammonia led to fast and clean conversion to the amino-substituted dyes; a hydroxyl-substituted Derivative was prepared by reaction with sodium ethylate, and thiol-substituted BODIPYs were obtained by reaction of 1a – 1f with potassium thioacetate followed by alkaline cleavage of the thioesters. Water-soluble Derivatives were prepared by introducing sulfonate groups into the 2- and 6-position of the BODIPY core. The synthesized BODIPY Derivatives showed high fluorescent yields and appeared to be stable under basic, reducing and oxidative conditions. As a proof of concept, 2-thioAdenosine was alkylated with bromoethyl-BODIPY 1b . The resulting fluorescent 2-substituted Adenosine Derivative 15 displayed selectivity for the A_3 Adenosine receptor (ARs) over the other AR subtypes, showed agonistic activity, and may thus become a useful tool for studying A_3ARs, or a lead structure for further optimization. The new functionalized dyes may be widely used for fluorescent labeling allowing the investigation of biological targets and processes.

  • nucleoside 5 monophosphates as prodrugs of Adenosine a2a receptor agonists activated by ecto 5 nucleotidase
    Journal of Medicinal Chemistry, 2009
    Co-Authors: Ali Eltayeb, Jamshed Iqbal, Andrea Behrenswerth, Michael Romio, Marion Schneider, Herbert Zimmermann, Jiirgen Schrader, Christa E. Müller
    Abstract:

    Prodrugs of Adenosine A2A receptor agonists were developed that are activated by ecto-5′-nucleotidase (ecto-5′-NT, CD73). Because ecto-5′-NT is upregulated in inflamed tissue, the A2A agonists are expected to be released from their prodrug form at the sites of inflammation. 2-(Ar)alkyl-substituted AMP Derivatives were synthesized and investigated. Certain 2-substituted AMP Derivatives, including 2-hexylthio-AMP, 2-cyclopentylthio-AMP, 2-cyclohexylmethylthio-AMP, and 2-cyclohexylethylthio-AMP were accepted as substrates by ecto-5′-NT and readily converted to the corresponding 2-substituted Adenosine Derivatives. The 2-cyclohexylethylthio substitution was a good compromise between the requirements of the ecto-5′-NT and the Adenosine A2A receptor. The corresponding AMP Derivative (12g) was a similarly good substrate as AMP itself, while the resulting Adenosine Derivative (11g) was a relatively potent A2A agonist (radioligand binding to rat brain striatal membranes: Ki = 372 nM; inhibition of anti-CD3/anti-CD…

Kenneth A. Jacobson – One of the best experts on this subject based on the ideXlab platform.

  • Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A_3 Adenosine receptor agonist that protects against chronic neuropathic pain
    Purinergic Signalling, 2015
    Co-Authors: Deepak K. Tosh, Janak Padia, Daniela Salvemini, Kenneth A. Jacobson
    Abstract:

    We reported that 2-(3,4-difluorophenylethynyl)- N ^6-3-chlorobenzyl ( N )-methanocarba Adenosine Derivative 1 (MRS5698) binds selectively to human and mouse A_3 Adenosine receptors (A_3ARs, K _ i 3 nM). It is becoming an important pharmacological tool for defining A_3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d -ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at

  • efficient large scale synthesis and preclinical studies of mrs5698 a highly selective a3 Adenosine receptor agonist that protects against chronic neuropathic pain
    Purinergic Signalling, 2015
    Co-Authors: Deepak K. Tosh, Janak Padia, Daniela Salvemini, Kenneth A. Jacobson
    Abstract:

    We reported that 2-(3,4-difluorophenylethynyl)-N 6-3-chlorobenzyl (N)-methanocarba Adenosine Derivative 1 (MRS5698) binds selectively to human and mouse A3 Adenosine receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t 1/2 of 1.09 h and plasma Cmax of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.

  • p53 independent induction of fas and apoptosis in leukemic cells by an Adenosine Derivative cl ib meca
    Biochemical Pharmacology, 2002
    Co-Authors: Seong Gon Kim, Gnana Ravi, Carsten Hoffmann, Yun Jin Jung, Min Kim, Aishe Chen, Kenneth A. Jacobson
    Abstract:

    Abstract A 3 Adenosine receptor (A 3 AR) agonists have been reported to influence cell death and survival. The effects of an A 3 AR agonist, 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9 H -purin-9-yl]-1-deoxy- N -methyl-β- d -ribofuranonamide (Cl-IB-MECA), on apoptosis in two human leukemia cell lines, HL-60 and MOLT-4, were investigated. Cl-IB-MECA (≥30 μM) increased the apoptotic fractions, as determined using fluorescence-activated cell sorting (FACS) analysis, and activated caspase 3 and poly-ADP-ribose-polymerase. Known messengers coupled to A 3 AR (phospholipase C and intracellular calcium) did not seem to play a role in the induction of apoptosis. Neither dantrolene nor BAPTA-AM affected the Cl-IB-MECA-induced apoptosis. Cl-IB-MECA failed to activate phospholipase C in HL-60 cells, while UTP activated it through endogenous P2Y 2 receptors. Induction of apoptosis during a 48 hr exposure to Cl-IB-MECA was not prevented by the A 3 AR antagonists [5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] (MRS 1220) or N -[9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5- c ]quinazolin-5-yl]benzeneacetamide (MRS 1523). Furthermore, higher concentrations of MRS 1220, which would also antagonize A 1 and A 2A receptors, were ineffective in preventing the apoptosis. Although Cl-IB-MECA has been shown in other systems to cause apoptosis through an A 3 AR-mediated mechanism, in these cells it appeared to be an Adenosine receptor-independent effect, which required prolonged incubation. In both HL-60 and MOLT-4 cells, Cl-IB-MECA induced the expression of Fas, a death receptor. This induction of Fas was not dependent upon p53, because p53 is not expressed in an active form in either HL-60 or MOLT-4 cells. Cl-IB-MECA-induced apoptosis in HL-60 cells was augmented by an agonistic Fas antibody, CH-11, and this increase was suppressed by the antagonistic anti-Fas antibody ZB-4. Therefore, Cl-IB-MECA induced apoptosis via a novel, p53-independent up-regulation of Fas.

Jian-jun Zhang – One of the best experts on this subject based on the ideXlab platform.

  • central Adenosine a1 receptor involved in the thermal regulation effect of yzg 330 a n6 substituted Adenosine Derivative in mice
    Acta pharmaceutica Sinica, 2015
    Co-Authors: Shao-bo Jia, Ying Zhang, Jiangong Shi, Jian-jun Zhang
    Abstract:

    Adenosine receptors (AR) play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline (a non-selective, blood-brain-barrier penetrably AR antagonist) could attenuate the effects of YZG-330 [(2R,3S,4R,5R)-2-(hydroxymethyl-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical Adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG-330 played on decreasing body temperature are in a dose-dependent manner: within the next 3 hour after intragastric administration (ig) of 0.25, 1 or 4 mg . kg-1 YZG-330, the extreme values on body temperature decreasing were (1.2 ± 0.3) °C, (3.6 ± 0.4) °C (P<0.001) and (7.4±0.5) °C (P<0.001), separately; whereas the duration that body temperature below 34 °C were 0, (10±5) and (153±4) min, separately. Adenosine A1 receptor (A1R) antagonist (DPCPX) could effectively reverse YZG-330’s effect on decreasing body temperature, with intraperitoneal administration of DPCPX (5 mg . kg-1) 20 min prior than YZG-330 (4 mg.kg-1, ig), the extreme value on body temperature decreasing was (3.5 ± 0.7) °C (P<0.001), the duration that body temperature below 34 °C was (8±6) min (P<0.001). However, Adenosine A2a receptor antagonist, SCH-58261, did not show any influence on the effects of YZG-330 at all. Combined with the fact that 8-SPT (a non-selective, blood-brain-barrier impenetrably AR antagonist) did not reverse the effect of YZG-330, we come to the conclusion that central-Adenosine A, receptor plays a significant role on the thermal regulation effect of YZG-330.

  • Central-Adenosine A1 receptor involved in the thermal regulation effect of YZG-330, a N6-substituted Adenosine Derivative, in mice
    Yao xue xue bao = Acta pharmaceutica Sinica, 2015
    Co-Authors: Shao-bo Jia, Ying Zhang, Jiangong Shi, Jian-jun Zhang
    Abstract:

    Adenosine receptors (AR) play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline (a non-selective, blood-brain-barrier penetrably AR antagonist) could attenuate the effects of YZG-330 [(2R,3S,4R,5R)-2-(hydroxymethyl-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical Adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG-330 played on decreasing body temperature are in a dose-dependent manner: within the next 3 hour after intragastric administration (ig) of 0.25, 1 or 4 mg . kg-1 YZG-330, the extreme values on body temperature decreasing were (1.2 ± 0.3) °C, (3.6 ± 0.4) °C (P

Victoria Chagoya De Sánchez – One of the best experts on this subject based on the ideXlab platform.

  • diminished s adenosylmethionine biosynthesis and its metabolism in a model of hepatocellular carcinoma is recuperated by an Adenosine Derivative
    Cancer Biology & Therapy, 2020
    Co-Authors: Maria Guadalupe Lozanorosas, Gabriela Velascoloyden, Lidia Martinezperez, Enrique Chavez, Mariana Dominguezlopez, Victoria Chagoya De Sánchez
    Abstract:

    S-adenosylmethionine (SAM), biosynthesis from methionine and ATP, is markedly decreased in hepatocellularular carcinoma (HCC) for a diminution in ATP levels, and the down regulation of the liver specific MAT1a enzyme. Its metabolic activity is very important in the transmethylation reactions, the methionine cycle, the biosynthesis of glutathione (GSH) and the polyamine pathway, which are markedly affected in the HCC. The chemo-preventive effect of IFC305 in HCC induced by DEN, and the increase of ATP and SAM in CCl4-induced cirrhosis have been previously demonstrated. The aim of this work was to test whether this chemo-preventive effect is mediated by the induction of SAM biosynthesis and its metabolic flow. SAM hepatic levels and the methionine cycle were recovered with IFC305 treatment, restoring transmethylation and transsulfuration activities. IFC305 treatment, increased MAT1a levels and decrease MAT2a levels through modulation of their post-transcriptional regulation. This occurred through the binding of the AUF1 (binding factor 1 AU-rich sites) and HuR (human antigen R) ribonucleoproteins to Mat1a and Mat2a messenger RNAs, which maintained their nuclear localization. Finally, the compound inhibited the polyamine pathway favoring the recuperation of the normal methionine and one carbon cycle recuperating the metabolic flow of methionine, which probably facilitated its HCC chemo-preventive effect.

  • Inflammation is regulated by the Adenosine Derivative molecule, IFC-305, during reversion of cirrhosis in a CCl4 rat model.
    International immunopharmacology, 2017
    Co-Authors: Rebeca Pérez-cabeza De Vaca, Jesús Rafael Rodríguez-aguilera, Nuria Guerrero-celis, Mariana Domínguez-lópez, Victoria Chagoya De Sánchez
    Abstract:

    Abstract Cirrhosis is a liver pathology originated by hepatocytes, Kupffer and hepatic stellate cells interactions and transformations. This pathology is associated with inflammation and fibrosis, originated by molecular signals secreted by immunological and parenchymal cells, such as cytokines and chemokines, like IL-1β, IL-6, TNF-α or MCP-1, driven by Kupffer cells signals. As part of inflammation resolution, the same activated Kupffer cells contribute to anti-inflammatory effects with IL-10 and MMP-9 secretion. In a Wistar rat<rat model, cirrhosis induced with CCl 4 is characterized by increased inflammatory cytokines, IL-6, IL-1β, MCP-1, and TNF-α, in plasma and liver tissue. The IFC-305 compound, an Adenosine Derivative salt, reverses the cirrhosis in this model, suggesting that immune mechanisms related to inflammation should be explored. The IFC-305 reduced inflammatory cytokines, supporting the anti-inflammatory effects induced by the elevation of IL-10, as well as the reduction of M1 inflammatory macrophages (CD11b/c + /CD163 + ) and the increase of M2 anti-inflammatory macrophages (HIS36 + /CD11b + ), measured by flow cytometry. Furthermore, the IFC-305 enhances the metabolic activity of arginase and moderates the inducible nitric oxide synthetase, evaluated through biochemical and immunohistochemical methods. These results contribute to understand the function of the IFC-305, which modulates the immune response in the Wistar rat<rat model of CCl 4 -induced cirrhosis and support the hepatic protective action through an anti-inflammatory effect, mainly mediated by Kupffer cells.

  • Cancer chemoprevention by an Adenosine Derivative in a model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats.
    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2017
    Co-Authors: Gabriela Velasco-loyden, Lidia Pérez-martínez, Susana Vidrio-gómez, Julio Isael Pérez-carreón, Victoria Chagoya De Sánchez
    Abstract:

    Hepatocellular carcinoma is one of the most common cancers, and approximately 80% develop from cirrhotic livers. We have previously shown that the aspartate salt of Adenosine prevents and reverses carbon tetrachloride-induced liver fibrfibrosis in rats. Considering the hepatoprotective role of this Adenosine Derivative in fibrogenesis, we were interested in evaluating its effect in a hepatocarcinogenesis model induced by diethylnitrosamine in rats, where multinodular cancer is preceded by cirrhosis. Rats were injected with diethylnitrosamine for 12 weeks to induce cirrhosis and for 16 weeks to induce hepatocarcinogenesis. Groups of rats were treated with aspartate salt of Adenosine from the beginning of carcinogen administration for 12 or 18 weeks total, and another group received the compound from weeks 12 to 18. Fibrogenesis was estimated and the proportion of preneoplastic nodules and tumors was measured. The apoptotic and proliferation rates in liver tissues were evaluated, as well as the expression of cell signaling and cell cycle proteins participating in hepatocarcinogenesis. The Adenosine Derivative treatment reduced diethylnitrosamine-induced collagen expression and decreased the proportion of nodules positive for the tumor marker γ-glutamyl transferase. This compound down-regulated the expression of thymidylate synthase and hepatocyte growth factor, and augmented the protein level of the cell cycle inhibitor p27; these effects could be part of its chemopreventive mechanism. These findings suggest a hepatoprotective role of aspartate salt of Adenosine that could be used as a therapeutic compound in the prevention of liver tumorigenesis as described earlier for hepatic fibrosis.

Shao-bo Jia – One of the best experts on this subject based on the ideXlab platform.

  • central Adenosine a1 receptor involved in the thermal regulation effect of yzg 330 a n6 substituted Adenosine Derivative in mice
    Acta pharmaceutica Sinica, 2015
    Co-Authors: Shao-bo Jia, Ying Zhang, Jiangong Shi, Jian-jun Zhang
    Abstract:

    Adenosine receptors (AR) play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline (a non-selective, blood-brain-barrier penetrably AR antagonist) could attenuate the effects of YZG-330 [(2R,3S,4R,5R)-2-(hydroxymethyl-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical Adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG-330 played on decreasing body temperature are in a dose-dependent manner: within the next 3 hour after intragastric administration (ig) of 0.25, 1 or 4 mg . kg-1 YZG-330, the extreme values on body temperature decreasing were (1.2 ± 0.3) °C, (3.6 ± 0.4) °C (P<0.001) and (7.4±0.5) °C (P<0.001), separately; whereas the duration that body temperature below 34 °C were 0, (10±5) and (153±4) min, separately. Adenosine A1 receptor (A1R) antagonist (DPCPX) could effectively reverse YZG-330’s effect on decreasing body temperature, with intraperitoneal administration of DPCPX (5 mg . kg-1) 20 min prior than YZG-330 (4 mg.kg-1, ig), the extreme value on body temperature decreasing was (3.5 ± 0.7) °C (P<0.001), the duration that body temperature below 34 °C was (8±6) min (P<0.001). However, Adenosine A2a receptor antagonist, SCH-58261, did not show any influence on the effects of YZG-330 at all. Combined with the fact that 8-SPT (a non-selective, blood-brain-barrier impenetrably AR antagonist) did not reverse the effect of YZG-330, we come to the conclusion that central-Adenosine A, receptor plays a significant role on the thermal regulation effect of YZG-330.

  • Central-Adenosine A1 receptor involved in the thermal regulation effect of YZG-330, a N6-substituted Adenosine Derivative, in mice
    Yao xue xue bao = Acta pharmaceutica Sinica, 2015
    Co-Authors: Shao-bo Jia, Ying Zhang, Jiangong Shi, Jian-jun Zhang
    Abstract:

    Adenosine receptors (AR) play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline (a non-selective, blood-brain-barrier penetrably AR antagonist) could attenuate the effects of YZG-330 [(2R,3S,4R,5R)-2-(hydroxymethyl-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical Adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG-330 played on decreasing body temperature are in a dose-dependent manner: within the next 3 hour after intragastric administration (ig) of 0.25, 1 or 4 mg . kg-1 YZG-330, the extreme values on body temperature decreasing were (1.2 ± 0.3) °C, (3.6 ± 0.4) °C (P