Identification of novel formyl peptide receptor-like 1 agonists that induce macrophage tumor necrosis factor alpha production.
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 alpha (TNF-alpha) 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-alpha 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 Ca(2+), production of reactive oxygen species, and chemotaxis in human and murine phagocytes. Induction of macrophage TNF-alpha 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 ). Overall, these compounds represent novel FPRL1 agonists that induce TNF-alpha, a response distinct from those induced by other known FPR and FPRL1 agonists.
Schepetkin
Igor A
IA
Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA.
Kirpotina
Liliya N
LN
Tian
Jun
J
Khlebnikov
Andrei I
AI
Ye
Richard D
RD
Quinn
Mark T
MT
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000096:biosynthesis; D044067:Receptors, Lipoxin / Q000819:agonists* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C105101:FPR2 protein, human; D004364:Pharmaceutical Preparations; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014409:Tumor Necrosis Factor-alpha