TY - JOUR T1 - A Novel Nonpeptide Ligand for Formyl Peptide Receptor-Like 1 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1213 LP - 1222 DO - 10.1124/mol.104.004309 VL - 66 IS - 5 AU - Masakatsu Nanamori AU - Xiyuan Cheng AU - Jianghua Mei AU - Hairong Sang AU - Yunxia Xuan AU - Caihong Zhou AU - Ming-Wei Wang AU - Richard D. Ye Y1 - 2004/11/01 UR - http://molpharm.aspetjournals.org/content/66/5/1213.abstract N2 - Formyl peptide receptor-like 1 (FPRL1) is a G protein-coupled receptor that binds natural and synthetic peptides as well as lipoxin A4 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 β-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 EC50 values of 7.17 × 10-8 M and 1.88 × 10-6 M, respectively, compared with the EC50 value for WKYMVm (2.29 × 10-8 M). However, Quin-C1 did not induce neutrophil superoxide generation at up to 100 μM. 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. ER -