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 [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.
Footnotes
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This project was supported in part by grants from the Ministry of Science and Technology of China (2004CB518902 to M.-W.W.), Chinese Academy of Sciences (KSCX1-SW-11-2 to M.-W.W.), Shanghai Municipality Science and Technology Development Fund (05DZ22914 and 06DZ22907 to M.-W.W.), and National Institutes of Health (AI033503 to R.D.Y.).
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C.Z. and S.Z. contributed equally to this work.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.037564.
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ABBREVIATIONS: FPR, formyl peptide receptor; FPRL1, formyl peptide receptor-like 1; SAR, structure-activity relationship; HTS, high-throughput screening; WKYMVm, Trp-Lys-Tyr-Met-Val-d-Met-NH2; WRW4, Trp-Arg-Trp-Trp-Trp-Trp-NH2; fMLF, N-formyl-Met-Leu-Phe; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; BSA, bovine serum albumin; NF-κB, nuclear factor-κB; ERK, extracellular signal-regulated kinase; DMSO, dimethyl sulfoxide; AA, arachidonic acid; GPCR, G protein-coupled receptor; HIV-1, human immunodeficiency virus-1; Quin-C1, 4-butoxy-N-[2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-benzamide.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. - Received April 27, 2007.
- Accepted July 25, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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