Received for publication April 30, 2007.
Revised July 25, 2007.
Accepted for publication July 25, 2007.

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 (HTS) campaign targeting the human formyl peptide receptor-like 1 (FPRL1). Based on structure-activity relationship (SAR) 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 methyoxyl substitution produced an agonist 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]WKYMVm binding to FPRL1 but not [³H]fMLF to FPR. In functional assays using FPRL1-expressing RBL-2H3 cells, C7 inhibited calcium mobilization and chemotaxis induced by WKYMVm and C1, as well as degranulation elicited by C1. C7 also suppressed C1-induced ERK 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.

Key words: Chemotactic peptides, Phosphorylation/Dephosphorylation, NFkappaB, Structure determinations