A novel nonpeptide ligand for formyl peptide receptor-like 1

doi:10.1124/mol.104.004309

	A novel nonpeptide ligand for formyl peptide receptor-like 1
	Nanamori, M ; Cheng, XY ; Mei, JH ; Sang, HR ; Xuan, YX ; Zhou, CH ; Wang, MW; Ye, RD
刊名	MOLECULAR PHARMACOLOGY
	2004-11
卷号	66 期号:5 页码:1213-1222
ISSN号	0026-895X
DOI	10.1124/mol.104.004309
文献子类	Article
英文摘要	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 EC50 values of 7.17 x 10(-8) M and 1.88 x 10(-6) M, respectively, compared with the EC50 value for WKYMVm (2.29 x 10(-8) M). However, Quin-C1 did not induce neutrophil superoxide generation at up to 100 muM. 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.
资助项目	NIAID NIH HHS[AI33503]
WOS关键词	PROTEIN-COUPLED RECEPTOR ; NF-KAPPA-B ; CHEMOATTRACTANT RECEPTOR ; HUMAN NEUTROPHILS ; PERTUSSIS TOXIN ; IDENTIFICATION ; CDNA ; ACTIVATION ; POTENT ; 7-TRANSMEMBRANE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000224578900015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/274001]
专题	中国科学院上海药物研究所
通讯作者	Ye, RD
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 200031, Peoples R China 2.Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA
推荐引用方式 GB/T 7714	Nanamori, M,Cheng, XY,Mei, JH,et al. A novel nonpeptide ligand for formyl peptide receptor-like 1[J]. MOLECULAR PHARMACOLOGY,2004,66(5):1213-1222.
APA	Nanamori, M.,Cheng, XY.,Mei, JH.,Sang, HR.,Xuan, YX.,...&Ye, RD.(2004).A novel nonpeptide ligand for formyl peptide receptor-like 1.MOLECULAR PHARMACOLOGY,66(5),1213-1222.
MLA	Nanamori, M,et al."A novel nonpeptide ligand for formyl peptide receptor-like 1".MOLECULAR PHARMACOLOGY 66.5(2004):1213-1222.