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Pharmacological Characterization of a Novel Nonpeptide Antagonist for Formyl Peptide Receptor-Like 1

The National Center for Drug Screening, Shanghai Institute of Materia Medica (C.Z., Y.Z., Q.L., N.L., M.S., M.-W.W.), and the Graduate School (S.Z.), Chinese Academy of Sciences, Shanghai, China; and Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois (M.N., J.T., P.P.Y., N.C., R.D.Y.)

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 [¹²⁵I]Trp-Lys-Tyr-Met-Val-D-Met-NH₂ (WKYMVm) binding to FPRL1 but not [³H]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.

Received for publication April 27, 2007.

Accepted for publication July 25, 2007.

Address correspondence to: Dr. Ming-Wei Wang, the National Center for Drug Screening, 189 Guo Shou Jing Road, Shanghai 201203, China. E-mail: mwwang{at}mail.shcnc.ac.cn

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