Discovery of Novel P2Y14 Agonist and Antagonist Using Conventional and Nonconventional Methods

Hamel, Martine; Hénault, Martin; Hyjazie, Huda; Morin, Nicolas; Bayly, Christopher I.; Skorey, Kathryn; Therien, Alex G.; Mancini, Joseph A.; Brideau, Christine; Kargman, Stacia

doi:10.1177/1087057111415525

Cited by 14 publications

(12 citation statements)

References 11 publications

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“…Hamel et al (2011) also screened a phosphonate library using a [ 3 H]UDP binding assay to identify several molecules that were concluded to bind to the P2Y 14 -R in the low micromolar range.…”

Section: Discussionmentioning

confidence: 99%

A Selective High-Affinity Antagonist of the P2Y₁₄ Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

Barrett

Sesma²,

Ball³

et al. 2013

Mol Pharmacol

128

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The nucleotide-sugar-activated P2Y 14 receptor (P2Y 14 -R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. ) that exhibited antagonist activity at the P2Y 14 -R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y 14 -R was shifted to the right in a concentration-dependent manner by PPTN.Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a K B of 434 pM observed. In contrast, 1 mM PPTN exhibited no agonist or antagonist effect at the P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , or P2Y 13 receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the K B determined with recombinant P2Y 14 -R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose-promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y 14 -R that is useful for interrogating the action of this receptor in physiologic systems.

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Section: Discussionmentioning

confidence: 99%

A Selective High-Affinity Antagonist of the P2Y₁₄ Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

Barrett

Sesma²,

Ball³

et al. 2013

Mol Pharmacol

128

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“…In contrast to other studies Carter et al demonstrated that uridine diphosphate acted also as agonist of human P2Y14R [22]. Intracellular calcium mobilization and nonconventional cellular impedance functional assays showed that UMP, UDP, and UTP uncoupled to glucose also activated P2Y14-expressing cells [23]. …”

Section: Resultsmentioning

confidence: 97%

“…Chambers et al reported that ADP-glucose, UMP, UDP, and UTP as well as uridine were unable to activate P2Y14 [21, 23]. The discovery by Carter et al that UDP also acts as a potent agonist revealed that a sugar moiety is not required for activation of the P2Y14 receptor.…”

Section: Introductionmentioning

confidence: 99%

“…In those studies slight activities were observed with ADP, CDP, and GDP at concentrations greater than 100-fold higher than the concentrations of UDP producing a maximal response [22, 24]. Hamel et al [23] showed with conventional and nonconventional methods that even UMP selectively activated HEK cells coexpressing P2Y14 and Gαqi5. The presence of 2-thiouracil modification within UDPG and UDP amplified potency at the human P2Y14 receptor with an EC 50 value of 11 nm and 1.92 nM, respectively, as compared to UDPG (EC 50 400 nM) and UDP (EC 50 160 nM) [25, 26].…”

Section: Introductionmentioning

confidence: 99%

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Nucleoside 5′-O-monophosphorothioates as modulators of the P2Y14 receptor and mast cell degranulation

et al. 2016

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Mast cells (MCs) are long-lived resident cells known for their substantial role in antigen-induced anaphylaxis and other immunoglobulin E-mediated allergic reactions as well as tumor promotion. MCs' activation results in the release of pro-inflammatory factors such as histamine, tryptase, tumor necrosis factor or carboxypeptidase A stored in secretory granules. IgE-dependent hypersensitivity has been thought to be the major pathway mediating degranulation of mast cells, but the P2Y14 nucleotide receptor activated by UDP-glucose (UDPG) may also enhance this process. In this study we identified thymidine 5'-O-monophosphorothioate (TMPS) as a molecule inhibiting UDPG-induced degranulation in a rat mast cell line (RBL-2H3). Additionally, TMPS diminished UDPG-evoked intracellular calcium mobilization in a stable HEK293T cell line overexpressing the P2Y14 receptor. Therefore, we demonstrate that the use of thymidine 5'-O-monophosphorothioate might be a novel anti-inflammatory approach based on preventingmast cell activation.

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“…Where antagonists used for animal studies, the substance is underlined and where clinical trials are ongoing is typed in bold. P2Y14 compound 18q, compound A, pro-drug 7j [10,12,52,60] prostaglandin [69] and EDHF [71,72] from ECs, might be responsible for the vasorelaxing effect. Since P2Y 2 activation causes the same vasorelaxation in eNOS -/-mice as it does in wild type mice, a major role of EDHF as mediator is implied [43].…”

Section: Purinoceptor Agonistsmentioning

confidence: 98%

P2Y Purinoceptors as Potential Emerging Therapeutical Target in Vascular Disease

Schuchardt

Tölle²,

Giet³

2012

CPD

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In the last two decades a tremendous development has been noticed in our understanding of the purinergic system, consisting of heterogeneously expressed purinoceptor subtypes and its classical agonists: e.g., adenosine triphosphate, uridine triphosphate or complex dinucleoside polyphosphates. These agonists exert multiple effects on the vascular system: they regulate the relaxation and constriction of arterial blood vessels, lead to proliferation and migration in endothelial cells and vascular smooth muscle cells, and mediate potent proinflammatory responses or phenotypic cell changes. This review focuses on the P2 purinoceptor subtype P2Y and its pleiotropic effects in the vascular wall under physiological and pathophysiological condition. Various experimental and clinical studies provide evidence that pharmacological targeting of P2Y might be effective in reducing vascular alterations under disease conditions.

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Discovery of Novel P2Y14 Agonist and Antagonist Using Conventional and Nonconventional Methods

Cited by 14 publications

References 11 publications

A Selective High-Affinity Antagonist of the P2Y₁₄ Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

A Selective High-Affinity Antagonist of the P2Y₁₄ Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

Nucleoside 5′-O-monophosphorothioates as modulators of the P2Y14 receptor and mast cell degranulation

P2Y Purinoceptors as Potential Emerging Therapeutical Target in Vascular Disease

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Discovery of Novel P2Y14 Agonist and Antagonist Using Conventional and Nonconventional Methods

Cited by 14 publications

References 11 publications

A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

Nucleoside 5′-O-monophosphorothioates as modulators of the P2Y14 receptor and mast cell degranulation

P2Y Purinoceptors as Potential Emerging Therapeutical Target in Vascular Disease

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A Selective High-Affinity Antagonist of the P2Y₁₄ Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

A Selective High-Affinity Antagonist of the P2Y₁₄ Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils