Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition

Liliya N. Kirpotina, Andrey Ivanovich Khlebnikov, Igor A. Schepetkin, Richard D. Ye, Marie Josèphe Rabiet, Mark A. Jutila, Mark T. Quinn

Research output: Contribution to journalArticle

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Abstract

N-formyl peptide receptor (FPR1) and N-formyl peptide receptor-like 1 (FPRL1, now known as FPR2) are G protein-coupled receptors involved in host defense and sensing cellular dysfunction. Because of the potential for FPR1/FPR2 as a therapeutic target, our recent high-throughput screening efforts have focused on the identification of unique nonpeptide agonists of FPR1/FPR2. In the present studies, we screened a chemolibrary of drug-like molecules for their ability to induce intracellular calcium mobilization in RBL-2H3 cells transfected with human FPR1 or FPR2. Screening of these compounds resulted in the identification of novel and potent agonists that activated both FPR1 and FPR2, as well as compounds that were specific for either FPR1 or FPR2 with EC50 values in the low micromolar range. Specificity of the compounds was supported by analysis of calcium mobilization in HL-60 cells transfected with human FPR1 and FPR2. In addition, all but one agonist activated intracellular calcium flux and chemotaxis in human neutrophils, irrespective of agonist specificity for FPR1 or FPR2. Molecular modeling of the group of FPR1 and FPR2 agonists using field point methodology allowed us to create pharmacophore models for ligand binding sites and formulate requirements for these specific N-formyl peptide receptor agonists. These studies further demonstrate that agonists of FPR1/ FPR2 include compounds with wide chemical diversity and that analysis of such compounds can enhance our understanding of their ligand/receptor interaction.

Original languageEnglish
Pages (from-to)159-170
Number of pages12
JournalMolecular Pharmacology
Volume77
Issue number2
DOIs
Publication statusPublished - Feb 2010
Externally publishedYes

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Formyl Peptide Receptor
Calcium
Ligands
Aptitude
HL-60 Cells
Chemotaxis
G-Protein-Coupled Receptors
Neutrophils
Binding Sites
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition. / Kirpotina, Liliya N.; Khlebnikov, Andrey Ivanovich; Schepetkin, Igor A.; Ye, Richard D.; Rabiet, Marie Josèphe; Jutila, Mark A.; Quinn, Mark T.

In: Molecular Pharmacology, Vol. 77, No. 2, 02.2010, p. 159-170.

Research output: Contribution to journalArticle

Kirpotina, Liliya N. ; Khlebnikov, Andrey Ivanovich ; Schepetkin, Igor A. ; Ye, Richard D. ; Rabiet, Marie Josèphe ; Jutila, Mark A. ; Quinn, Mark T. / Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition. In: Molecular Pharmacology. 2010 ; Vol. 77, No. 2. pp. 159-170.
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