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Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor Production

Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana (I.A.S., L.N.K., M.T.Q.); Department of Pharmacology, University of Illinois, Chicago, Illinois (J.T., R.D.Y.); and Department of Chemistry, Altai State Technical University, Barnaul, Russia (A.I.K.)

Development of immunomodulatory agents that enhance innate immune responses represents a promising strategy for combating infectious diseases. In the present studies, we screened a series of 71 arylcarboxylic acid hydrazide derivatives for their ability to induce macrophage tumor necrosis factor (TNF-) production and identified six such compounds, including one compound previously shown to be a formyl peptide receptor (FPR/FPRL1) agonist. The two most potent compounds [compound 1, nicotinic acid [5-(3-bromophenyl)-2-furyl]methylene-hydrazide; compound 2, 4-fluoro-benzoic acid [5-(3-trifluoromethyl-phenyl)-2-furyl]-methylene-hydrazide] were selected for further analysis. These compounds induced de novo production of TNF- in a dose- and time-dependent manner in human and murine monocyte/macrophage cell lines and in primary macrophages. These compounds also induced mobilization of intracellular Ca²⁺, production of reactive oxygen species, and chemotaxis in human and murine phagocytes. Induction of macrophage TNF- production was pertussis toxin-sensitive, and analysis of the cellular target of these compounds showed that they were FPRL1-specific agonists and that this response was blocked by FPR/FPRL1 and FPRL1-specific antagonists. In addition, pharmacophore modeling showed a high degree of similarity for low-energy conformations of these two compounds to the current pharmacophore model for FPR ligands ( Mol Pharmacol 68: 1301-1310, 2005[Abstract/Free Full Text] ). Overall, these compounds represent novel FPRL1 agonists that induce TNF-, a response distinct from those induced by other known FPR and FPRL1 agonists.

Address correspondence to: Dr. Mark T. Quinn, Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, Phone: 406-994-5721; Fax 406-994-4303, E-mail: mquinn{at}montana.edu