Inhibition of Ecto-ATPase by the P2Purinoceptor Agonists, ATPγS, α,β-Methylene-ATP, and AMP-PNP, in Endothelial Cells

Chen, Bing Chang; Lin, Wan-Wan

doi:10.1006/bbrc.1997.6478

Cited by 32 publications

(19 citation statements)

References 20 publications

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“…β,γ-CH 2 –ATP and analogues have been evaluated as metabolically stable ligands for certain P2 receptor sub-types [35,41–45]. For instance, β,γ-CH 2 –ATP was found to be a P2X 1 R agonist [46,47], but a weak agonist at P2X 2/3 Rs [35].…”

Section: Resultsmentioning

confidence: 99%

Identification of hydrolytically stable and selective P2Y1 receptor agonists

Eliahu

Camden

Lecka

et al. 2009

European Journal of Medicinal Chemistry

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P2Y nucleotide receptors (P2YRs) are attractive pharmaceutical targets. Most P2YR agonists proposed as drugs consist of a nucleotide scaffold, but their use is limited due to their chemical and enzymatic instabilities. To identify drug candidates, we developed non-hydrolyzable P2YR agonists. We synthesized ATP-β,γ-CH2 analogues 2–4, and evaluated their chemical and metabolic stabilities and activities at P2Y1,2,4,6 receptors. Analogues 2–4 exhibited t1/2 values of 14.5–65 h in gastric juice pH. They were completely resistant to alkaline phosphatase for 30 min at 37 °C and slowly hydrolyzed in human blood serum (t1/2 12.7–71.9 h). In comparison to ATP, analogues 2–4 were barely hydrolyzed by nucleoside triphosphate diphosphohydrolases, NTPDase1,2,3,8 (<8% hydrolysis), and nucleotide pyrophosphatases, NPP1,3 ( 10% hydrolysis). Analogues 2 and 4B were selective agonists of the P2Y1R with EC50s of 0.08 and 17.2 μM, respectively. These features make analogues 2 and 4B potential therapeutic agents for health disorders involving the P2Y1R.

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Section: Resultsmentioning

confidence: 99%

Identification of hydrolytically stable and selective P2Y1 receptor agonists

Eliahu

Camden

Lecka

et al. 2009

European Journal of Medicinal Chemistry

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“…First, 5Ј-FSBA inhibits E-NTPDase activity and type 1 cytokine secretion, but it does not agonize (or antagonize) P2 receptors (37). Second, ATP␥S inhibits E-NTPDase activity (36,38) and secretion of type 1 cytokines, whereas ATP␥S is an agonist of P2 receptors (4,39). Thus, inhibition of cytokine secretion correlates with the antagonism of E-NTPDase rather than the ability to activate P2 receptors.…”

Section: Discussionmentioning

confidence: 97%

Secretion of IL-2 and IFN-γ, But Not IL-4, by Antigen-Specific T Cells Requires Extracellular ATP

Langston

Gewirtz

et al. 2003

The Journal of Immunology

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Extracellular ATP and other nucleotides transmit signals to cells via surface-associated molecules whose binding sites face the extracellular milieu. Ecto-nucleoside triphosphate diphosphohydrolase is such an ATP-binding enzyme that is expressed by activated lymphocytes. We have previously shown that nonhydrolyzable ATP analogs block the lytic activity of NK cells and CD8+ T cells as well as their E-NTPDase activity. These results suggest that the hydrolysis of ATP may play a role in lymphocyte function. Here we report that E-NTPDase activity is up-regulated within 15 min of T cell stimulation and that reversible and irreversible enzyme inhibitors profoundly reduce secretion of IL-2 and IFN-γ, but not IL-4. TNF-α, IL-10, and IL-5 production showed intermediate sensitivity to these ATP analogs. Depletion of extracellular ATP also inhibited secretion of IFN-γ, but not IL-4, supporting the interpretation that extracellular ATP is required for secretion of some, but not all, cytokines. E-NTPDase antagonists reduced transcription of IL-2 mRNA and inhibited TCR-mediated intracellular calcium flux. These results suggest that extracellular ATP plays an essential role in the TCR-mediated signal transduction cascade for expression of certain cytokine genes.

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“…The lack of homogeneity in the distribution of a particular surface molecule on individuals of the same isolate or clone is characteristic of Trypanosoma cruzi (De Souza 1989) and can reflect differences in infectivity, as shown by Pereira et al (1996). The ecto-ATPase activity can be inhibited by the impermeant agent DIDS (Knowles 1988;Plesner 1995;Barbacci et al 1996;Meyer-Fernandes et al 1997) and by suramin, a polyanionic compound with known anti-parasitic activities that has been shown to be a P2 receptor-antagonist (Chen and Lin 1997). Suramin has also been found to interfere with the mitogenic signaling of P2 receptors to MAP kinases (Neary et al 1998), to interfere with the binding of growth factors to their receptors at the cell surface (Middaugh et al 1992) and to inhibit nuclear enzymes and other intracellular enzymatic systems (Voogd et al 1993;Eisenberger and Reyno 1994).…”

Section: Discussionmentioning

confidence: 99%

Ecto-ATPase activity on the surface of Trypanosoma cruzi and its possible role in the parasite?host cell interaction

Bisaggio

Peres-Sampaio

Meyer‐Fernandes

et al. 2003

Parasitology Research

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This study describes the possible role of Mg(2+)-dependent ecto-ATPase activity on the Trypanosoma cruzi-host cell interaction. Mg(2+)-dependent ecto-ATPase activity is observed on the cell body and flagellar membranes of the parasite and is about 20 times greater in trypomastigotes, as compared with epimastigotes. Suramin (a competitive antagonist of P2 receptors) and the impermeant agent 4,4'-diisothiocyanostylbene 2',2'-disulfonic acid (DIDS), both inhibitors of ecto-ATPases, strongly inhibited ATPase activity and the adhesion and internalization of both evolutive forms by mouse resident macrophages. Suramin inhibited the growth of epimastigotes, suggesting a direct participation of ecto-ATPase activity in this process. To overcome the presence of suramin in the culture medium during the time of growth, Mg(2+) ecto-ATPase activity was enhanced 4-fold, as compared with control parasites. The over-expression in enzyme activity was followed by a dramatic increase in the adhesion of epimastigotes to resident macrophages above the level observed for non-treated parasites.

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Inhibition of Ecto-ATPase by the P2Purinoceptor Agonists, ATPγS, α,β-Methylene-ATP, and AMP-PNP, in Endothelial Cells

Cited by 32 publications

References 20 publications

Identification of hydrolytically stable and selective P2Y1 receptor agonists

Identification of hydrolytically stable and selective P2Y1 receptor agonists

Secretion of IL-2 and IFN-γ, But Not IL-4, by Antigen-Specific T Cells Requires Extracellular ATP

Ecto-ATPase activity on the surface of Trypanosoma cruzi and its possible role in the parasite?host cell interaction

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