title: Pharmacological characterization of a novel nonpeptide antagonist for formyl peptide receptor-like 1.
abstract: A series of quinazolinone derivatives were synthesized based on a hit compound identified from a high-throughput screening campaign targeting the human formyl peptide receptor-like 1 (FPRL1). Based on structure-activity relationship analysis, we found that substitution on the para position of the 2-phenyl group of the quinazolinone backbone could alter the pharmacological properties of the compound. The methoxyl substitution produced an agonist 4-butoxy-N-[2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-benzamide (Quin-C1; C1), whereas a hydroxyl substitution resulted in a pure antagonist, Quin-C7 (C7). Several partial agonists were derived from other substitutions on the para position. C7 partially displaced [(125)I]Trp-Lys-Tyr-Met-Val-d-Met-NH(2) (WKYMVm) binding to FPRL1 but not [(3)H]N-formyl-Met-Leu-Phe to formyl peptide receptor. In functional assays using FPRL1-expressing RBL-2H3 cells, C7 inhibited calcium mobilization and chemotaxis induced by WKYMVm and C1 and degranulation elicited by C1. C7 also suppressed C1-induced extracellular signal-regulated kinase phosphorylation and reduced arachidonic acid-induced ear edema in mice. This study represents the first characterization of a nonpeptidic antagonist for FPRL1 and suggests the prospect of using low molecular weight compounds as modulators of chemoattractant receptors in vitro and in vivo.
authors.affiliation: National Center for Drug Screening, 189 Guo Shou Jing Road, Shanghai 201203, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Zhou
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Nanamori
authors.forename: Yueyun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Meiling
authors.initials: M
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Ye
authors.forename: Ni
authors.initials: N
authors.lastname: Cheng
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
mesh_terms: D016718:Arachidonic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D002630:Chemotactic Factors; C469986:FPR1 protein, human; D008024:Ligands; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; C113617:Trp-Lys-Tyr-Met-Val-Met; D016718:Arachidonic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium