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Research ArticleCELLULAR AND MOLECULAR

Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Dean Y. Maeda, Mark T. Quinn, Igor A. Schepetkin, Liliya N. Kirpotina and John A. Zebala
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 145-152; DOI: https://doi.org/10.1124/jpet.109.159020
Dean Y. Maeda
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Mark T. Quinn
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Igor A. Schepetkin
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Liliya N. Kirpotina
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John A. Zebala
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Abstract

The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and ester forms of the nicotinamide glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. Ester forms of the nicotinamide glycolate antagonized CXCL1-stimulated chemotaxis (IC50 = 42 nM) and calcium flux (IC50 = 48 nM) in human neutrophils, but they were inactive in cell-free assays of 125I-CXCL8/CXCR2 binding and CXCL1-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) exchange. Acid forms of the nicotinamide glycolate were inactive in whole-cell assays of chemotaxis and calcium flux, but they inhibited 125I-CXCL8/CXCR2 binding and CXCL1-stimulated [35S]GTPγS exchange. The 3H ester was internalized by neutrophils and rapidly converted to the 3H acid in a concentrative process. The 3H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide glycolate ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential.

Footnotes

  • This work was supported in part by the National Institutes of Health National Heart Lung and Blood Institute [Grant R44-HL072614] (to D.Y.M.); and the National Institutes of Health National Center for Research Resources [Grant RR020185] (to M.T.Q.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.159020

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PMN
    polymorphonuclear leukocyte
    CXC
    Cys-Xaa-Cys
    SB265610
    [1-(2-bromo-phenyl)-3-(7-cyano-3H-benzotriazol-4-yl)-urea]
    SCH527123
    [2-hydroxy-N,N,-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide]
    CCR1/2/3/9
    chemokine (C-C motif) receptor 9
    CXCL1/2/3
    growth-related oncogenes α, β, and γ (GRO α/β/γ)
    CXCL5
    epithelial-derived neutrophil-activating peptide 78 (ENA-78)
    CXCL6
    granulocyte chemotactic protein-2
    CXCL7
    neutrophil-activating protein-2 (NAP-2)
    CXCL8
    interleukin-8
    OAT
    organic anion transporter
    HBSS
    Hanks' balanced salt solution
    HBSS−
    HBSS without Ca2+ and Mg2+
    HPLC
    high-performance liquid chromatography
    CHO
    Chinese hamster ovary
    DMSO
    dimethyl sulfoxide
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    ANOVA
    analysis of variance
    AMD3100
    1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane] octohydrobromide dehydrate
    BX471
    N-(5-chloro-2-(2-(4-((4-fluorophenyl)methyl)-2-methyl-1-piperazinyl)-2-oxoethoxy) phenyl)urea hydrochloric acid
    TAK-799
    (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbon-yl]amino]benzyl]-tetrahydro-2H-pyran4-aminium chloride
    Compound 1
    [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanyl]-acetic acid methyl ester
    Compound 2
    [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanyl]-acetic acid
    Compound 3
    [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid methyl ester
    Compound 4
    [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid
    Compound 5
    [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanyl]-acetic acid benzyl ester
    and Compound 6
    [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanyl] acetic acid tert-butyl ester
    Compound 7
    5,6-dichloro-N-(4-fluoro-phenyl)-nicotinamide
    Compound 8
    [3-chloro-5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanyl]-acetic acid methyl ester
    Compound 9
    [3-chloro-5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanyl]-acetic acid.

    • Received July 19, 2009.
    • Accepted September 24, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleCELLULAR AND MOLECULAR

Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Dean Y. Maeda, Mark T. Quinn, Igor A. Schepetkin, Liliya N. Kirpotina and John A. Zebala
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 145-152; DOI: https://doi.org/10.1124/jpet.109.159020

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Research ArticleCELLULAR AND MOLECULAR

Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Dean Y. Maeda, Mark T. Quinn, Igor A. Schepetkin, Liliya N. Kirpotina and John A. Zebala
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 145-152; DOI: https://doi.org/10.1124/jpet.109.159020
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