A novel nonpeptide ligand for formyl peptide receptor-like 1.
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.
Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, M/C 868, Chicago, IL 60612, USA.
Masakatsu
M
Nanamori
Xiyuan
X
Cheng
Jianghua
J
Mei
Hairong
H
Sang
Yunxia
Y
Xuan
Caihong
C
Zhou
Ming-Wei
MW
Wang
Richard D
RD
Ye
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D004347:Drug Interactions; D004705:Endocytosis / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured
C493592:4-butoxy-N-(2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl)-benzamide; D001549:Benzamides; D008024:Ligands; D009842:Oligopeptides; D011799:Quinazolines; D044042:Receptors, Formyl Peptide; C113617:Trp-Lys-Tyr-Met-Val-Met; D013481:Superoxides; D020928:Mitogen-Activated Protein Kinases; D005966:Glucuronidase; D019206:GTP-Binding Protein alpha Subunits, Gi-Go