A novel nonpeptide ligand for formyl peptide receptor-like 1.

Abstract

Formyl peptide receptor-like 1 (FPRL1) is a G protein-coupled receptor that binds natural and synthetic peptides as well as lipoxin A(4) and mediates important biological functions. To facilitate its pharmacological characterization, we screened a compound library and identified a substituted quinazolinone (Quin-C1, 4-butoxy-N-[2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-benzamide) as a ligand for FPRL1. Quin-C1 induces chemotaxis and secretion of beta-glucuronidase in peripheral blood neutrophils with a potency of approximately 1/1000 of that of the peptide agonist WKYMVm. In studies using transfected rat basophilic leukemia (RBL) cell lines expressing either formyl peptide receptor or FPRL1, Quin-C1 induced enzyme release from RBL-FPRL1 but not RBL-FPR cells. Likewise, Quin-C1 selectively stimulates calcium mobilization in RBL-FPRL1 cells, a response that was markedly inhibited by pertussis toxin. Quin-C1 also stimulates phosphorylation of extracellular signal-regulated protein kinases 1 and 2 and induces internalization of an FPRL1 fused to green fluorescent protein. In degranulation assays, both the FPRL1-selective peptide agonist MMK1 and Quin-C1 exhibited lower efficacy and potency than WKYMVm, with EC(50) values of 7.17 x 10(-8) M and 1.88 x 10(-6) M, respectively, compared with the EC(50) value for WKYMVm (2.29 x 10(-8) M). However, Quin-C1 did not induce neutrophil superoxide generation at up to 100 microM. Based on these results, we conclude that Quin-C1 is a novel nonpeptide ligand that binds to FPRL1 and selectively stimulates FPRL1-mediated functions. Quin-C1 is a prototype of substituted quinazolinones based on which further structural modifications may be made to improve its efficacy and potency for FPRL1.

• Authors: Masakatsu Nanamori, Xiyuan Cheng, Jianghua Mei, Hairong Sang, Yunxia Xuan, Caihong Zhou, Ming-Wei Wang, Richard D Ye
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 66 Issue 5 Pg. 1213-22 (Nov 2004) ISSN: 0026-895X [Print] United States
• PMID: 15308762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 4-butoxy-N-(2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl)-benzamide
• Benzamides
• Ligands
• Oligopeptides
• Quinazolines
• Receptors, Formyl Peptide
• Trp-Lys-Tyr-Met-Val-Met
• Superoxides
• Mitogen-Activated Protein Kinases
• Glucuronidase
• GTP-Binding Protein alpha Subunits, Gi-Go

Topics

• Animals
• Benzamides (chemical synthesis, pharmacology)
• Cell Line
• Chemotaxis (drug effects)
• Drug Interactions
• Endocytosis (drug effects)
• GTP-Binding Protein alpha Subunits, Gi-Go (physiology)
• Glucuronidase (metabolism)
• Humans
• Ligands
• Mitogen-Activated Protein Kinases (metabolism)
• Neutrophils (drug effects, metabolism)
• Oligopeptides (pharmacology)
• Phosphorylation (drug effects)
• Quinazolines (chemical synthesis, pharmacology)
• Rats
• Receptors, Formyl Peptide (agonists, metabolism)
• Signal Transduction (drug effects)
• Superoxides (metabolism)
• Tumor Cells, Cultured