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.
Nanamori
Masakatsu
M
Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, M/C 868, Chicago, IL 60612, USA.
Cheng
Xiyuan
X
Mei
Jianghua
J
Sang
Hairong
H
Xuan
Yunxia
Y
Zhou
Caihong
C
Wang
Ming-Wei
MW
Ye
Richard D
RD
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