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Research ArticleArticle

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

Igor A. Schepetkin, Liliya N. Kirpotina, Andrei I. Khlebnikov, Mark A. Jutila and Mark T. Quinn
Molecular Pharmacology January 2011, 79 (1) 77-90; DOI: https://doi.org/10.1124/mol.110.068288
Igor A. Schepetkin
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Liliya N. Kirpotina
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Andrei I. Khlebnikov
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Mark A. Jutila
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Mark T. Quinn
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Abstract

N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in host defense and sensing cellular dysfunction. Thus, FPRs represent important therapeutic targets. In the present studies, we screened 32 ligands (agonists and antagonists) of unrelated GPCRs for their ability to induce intracellular Ca2+ mobilization in human neutrophils and HL-60 cells transfected with human FPR1, FPR2, or FPR3. Screening of these compounds demonstrated that antagonists of gastrin-releasing peptide/neuromedin B receptors (BB1/BB2) PD168368 [(S)-a-methyl-a-[[[(4-nitrophenyl)amino]carbonyl]amino]-N-[[1-(2-pyridinyl) cyclohexyl]methyl]-1H-indole-3-propanamide] and PD176252 [(S)-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]-a-methyl-a-[[-(4-nitrophenyl)amino]carbonyl]amino-1H-indole-3-propanamide] were potent mixed FPR1/FPR2 agonists, with nanomolar EC50 values. Cholecystokinin-1 receptor agonist A-71623 [Boc-Trp-Lys(ε-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH2] was also a mixed FPR1/FPR2 agonist, but with a micromolar EC50. Screening of 56 Trp- and Phe-based PD176252/PD168368 analogs and 41 related nonpeptide/nonpeptoid analogs revealed 22 additional FPR agonists. Most were potent mixed FPR1/FPR2/FPR3 agonists with nanomolar EC50 values for FPR2, making them among the most potent nonpeptide FPR2 agonists reported to date. In addition, these agonists were also potent chemoattractants for murine and human neutrophils and activated reactive oxygen species production in human neutrophils. Molecular modeling of the selected agonists using field point methods allowed us to modify our previously reported pharmacophore model for the FPR2 ligand binding site. This model suggests the existence of three hydrophobic/aromatic subpockets and several binding poses of FPR2 agonists in the transmembrane region of this receptor. These studies demonstrate that FPR agonists could include ligands of unrelated GPCR and that analysis of such compounds can enhance our understanding of pharmacological effects of these ligands.

Footnotes

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

  • This work was supported in part by the National Institutes of Health National Center for Research Resources [Grant P20-RR020185]; by the National Institutes of Health [Contract HHSN266200400009C]; the M. J. Murdock Charitable Trust; and the Montana State University Agricultural Experimental Station.

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

    doi:10.1124/mol.110.068288.

  • ABBREVIATIONS:

    fMLF
    N-formyl-methionyl-leucyl-phenyalanine
    FPR
    formyl peptide receptor
    GPCR
    G protein-coupled receptor
    SAR
    structure-activity relationship
    ROS
    reactive oxygen species
    L-012
    8-amino-5-chloro-7-phenylpyridol[3,4-d]pyridazine-1,4(2H,3H)-dione
    DMSO
    dimethyl sulfoxide
    WKYMVm
    Trp-Lys-Tyr-Met-Val-d-Met
    HBSS
    Hanks' balanced salt solution
    HBSS+
    Hanks' balanced salt solution containing 1.3 mM CaCl2 and 1.0 mM MgSO4
    AM
    acetoxymethyl ester
    MPO
    myeloperoxidase
    CCK
    cholecystokinin
    TM
    transmembrane
    PD168368
    (S)-a-methyl-a-[[[(4-nitrophenyl)amino]carbonyl]amino]-N-[[1-(2-pyridinyl) cyclohexyl]methyl]-1H-indole-3-propanamide
    PD176252
    (S)-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]-a-methyl-a-[[-(4-nitrophenyl)amino]carbonyl]amino-1H-indole-3-propanamide
    A-71623
    Boc-Trp-Lys(ε-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH2
    NNC 63-0532
    (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro(4.5)-dec-3-yl)acetic acid methyl ester
    SR 27897
    1-((2-(4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl)indolyl)acetic acid
    YM 022
    1-(2,3-dihydro-1-(2′-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(3-methylphenyl)urea
    LY 288513
    1-(4-bromophenylaminocarbonyl)-4,5-diphenyl-3-pyrazolidinone
    BML-190
    indomethacin morpholinylamide
    AM 630
    iodopravadoline
    GW 405833
    1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole
    S 25585
    1-benzoyl-2-[[trans-4-[[[[2-nitro-4-trifluoromethyl)phenyl]sulfonyl]amino]methyl]cyclohexyl]carbonyl]hydrazine
    SR 49059
    relcovaptan
    AC 55541
    (2E)-2-[1-(3-bromo-phenyl)ethylidene] α-(benzoylamino)-3,4-dihydro-4-oxo-1-phthalazineacetic acid hydrazide
    JTE 013
    1-[1,3-dimethyl-4-(2-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-4-(3,5-dichloro-4-pyridinyl)-semicarbazide
    RF9
    adamantylcarbonyl-arginyl-phenylalaninamide
    SR 142948
    2-[[[5-(2,6-dimethoxyphenyl)-1-[4- [[[3-(dimethylamino)propyl]methylamino]carbonyl]-2-(1-methylethyl)phenyl]-1H-pyrazol-3-yl]carbonyl]amino]-tricyclo[3.3.1.13,7]decane-2-carboxylic acid
    FR 139317
    N-(N-(N-((hexahydro-1H-azepin-1-yl)carbonyl)-l-leucyl)-1-methyl-d-tryptophyl)-3-(2-pyridinyl)-d-alanine
    ONO 1078
    pranlukast
    L-692,585
    3-[[(2R)-2-hydroxypropyl]amino]-3-methyl-N-[(3R)-2,3,4,5-tetrahydro-2-oxo-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3-yl]-butanamide
    T 98475
    7-[(2,6-difluorophenyl)methyl]-4,7-dihydro-2-[4-[(2-methyl-1-oxopropyl)amino]phenyl]-3-[[methyl(phenylmethyl)amino]methyl]-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid 1-methylethyl ester
    L-371,257
    1-(1-(4-((N-acetyl-4-piperidinyl)oxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one
    FK 888
    N(2)-(4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl)-N-methyl-N-phenylmethyl-3-(2-naphthyl)-l-alaninamide
    SDZ NKT 343
    2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide
    L-732,138
    N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester
    WEB 2086
    apafant
    L-161,982
    N-[[4′-[[3-butyl-1,5-dihydro-5-oxo-1-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-4-yl]methyl][1,1′-biphenyl]-2-yl]sulfonyl]-3-methyl-2-thiophenecarboxamide
    L-054,264
    2-((spiro(1H-indene-1,4′-piperidin)-1′-ylcarbonyl)amino)-N-(3-aminomethyl-1-cyclohexylmethyl)-3-(1H-indol-3-yl)propanamide
    BIM 187
    1-de(5-oxo-l-proline)-2-de-l-valine-3-d-phenylalanine-10-l-leucine-11-l-leucinamide-ranatensin
    BIM 189
    1-de(5-oxo-l-proline)-2-de-l-valine-3-d-phenylalanine-10-l-leucine-11-(4-chloro-l-phenylalaninamide)-ranatensin
    BIM 23042
    d-Nal-Cys-Tyr-d-Trp-Lys-Val-Cys-Nal-NH2
    BIM 23127
    d-Nal-Cys-Tyr-d-Trp-Orn-Val-Cys-Nal-NH2
    ICI 216,140
    N-isobutyryl-His-Trp-Ala-Val-d-Ala-His-Leu-NHMe
    PD165929
    2-[3-(2, 6-diisopropyl-phenyl)-ureido]3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-proprionate
    Frohn-11
    1-((5-methoxyindol-2-yl)carbonyl)-3-(2-ethylbenzimidazol-1-yl)(3R)pyrrolidine
    Bürli-25
    N-(4-bromophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)urea
    Cilibrizzi-14x
    N-(4-bromophenyl)-2-[5-(4-methoxybenzyl)-3-methyl-6-oxo-6H-pyridazin-1-yl]-acetamide
    NCGC00168126–01
    N-(4-(5-(3-(furan-2-ylmethyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)-2-methoxybenzyloxy)phenyl acetamide.

  • Received August 18, 2010.
  • Accepted October 13, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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1 Jan 2011
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Research ArticleArticle

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

Igor A. Schepetkin, Liliya N. Kirpotina, Andrei I. Khlebnikov, Mark A. Jutila and Mark T. Quinn
Molecular Pharmacology January 1, 2011, 79 (1) 77-90; DOI: https://doi.org/10.1124/mol.110.068288

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Research ArticleArticle

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

Igor A. Schepetkin, Liliya N. Kirpotina, Andrei I. Khlebnikov, Mark A. Jutila and Mark T. Quinn
Molecular Pharmacology January 1, 2011, 79 (1) 77-90; DOI: https://doi.org/10.1124/mol.110.068288
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