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Molecular Pharmacology

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Research ArticleArticle

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

Matthew O. Barrett, Juliana I. Sesma, Christopher B. Ball, P. Suresh Jayasekara, Kenneth A. Jacobson, Eduardo R. Lazarowski and T. Kendall Harden
Molecular Pharmacology July 2013, 84 (1) 41-49; DOI: https://doi.org/10.1124/mol.113.085654
Matthew O. Barrett
Departments of Pharmacology (M.O.B., C.B.B., T.K.H.) and Medicine (J.I.S., E.R.L.), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (P.S.J., K.A.J.)
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Juliana I. Sesma
Departments of Pharmacology (M.O.B., C.B.B., T.K.H.) and Medicine (J.I.S., E.R.L.), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (P.S.J., K.A.J.)
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Christopher B. Ball
Departments of Pharmacology (M.O.B., C.B.B., T.K.H.) and Medicine (J.I.S., E.R.L.), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (P.S.J., K.A.J.)
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P. Suresh Jayasekara
Departments of Pharmacology (M.O.B., C.B.B., T.K.H.) and Medicine (J.I.S., E.R.L.), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (P.S.J., K.A.J.)
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Kenneth A. Jacobson
Departments of Pharmacology (M.O.B., C.B.B., T.K.H.) and Medicine (J.I.S., E.R.L.), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (P.S.J., K.A.J.)
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Eduardo R. Lazarowski
Departments of Pharmacology (M.O.B., C.B.B., T.K.H.) and Medicine (J.I.S., E.R.L.), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (P.S.J., K.A.J.)
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T. Kendall Harden
Departments of Pharmacology (M.O.B., C.B.B., T.K.H.) and Medicine (J.I.S., E.R.L.), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (P.S.J., K.A.J.)
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Abstract

The nucleotide-sugar–activated P2Y14 receptor (P2Y14-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. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y14-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 P2Y14-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 KB of 434 pM observed. In contrast, 1 μM PPTN exhibited no agonist or antagonist effect at the P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, or P2Y13 receptors. UDP-glucose–promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the KB determined with recombinant P2Y14-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 P2Y14-R that is useful for interrogating the action of this receptor in physiologic systems.

Footnotes

    • Received February 14, 2013.
    • Accepted April 12, 2013.
  • This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM38213]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL34322]; and the Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases].

  • dx.doi.org/10.1124/mol.113.085654.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 84 (1)
Molecular Pharmacology
Vol. 84, Issue 1
1 Jul 2013
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Research ArticleArticle

Selective High-Affinity P2Y14 Receptor Antagonist

Matthew O. Barrett, Juliana I. Sesma, Christopher B. Ball, P. Suresh Jayasekara, Kenneth A. Jacobson, Eduardo R. Lazarowski and T. Kendall Harden
Molecular Pharmacology July 1, 2013, 84 (1) 41-49; DOI: https://doi.org/10.1124/mol.113.085654

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Research ArticleArticle

Selective High-Affinity P2Y14 Receptor Antagonist

Matthew O. Barrett, Juliana I. Sesma, Christopher B. Ball, P. Suresh Jayasekara, Kenneth A. Jacobson, Eduardo R. Lazarowski and T. Kendall Harden
Molecular Pharmacology July 1, 2013, 84 (1) 41-49; DOI: https://doi.org/10.1124/mol.113.085654
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