title: Novel agonists and antagonists for human protease activated receptor 2.
abstract: Human protease activated receptor 2 (PAR2) is a G protein-coupled receptor that is associated with inflammatory diseases and cancers. PAR2 is activated by serine proteases that cleave its N-terminus and by synthetic peptides corresponding to the new N-terminus. Peptide agonists are widely used to characterize physiological roles for PAR2 but typically have low potency (e.g., SLIGKV-NH(2), SLIGRL-NH(2)), uncertain target selectivity, and poor bioavailability, limiting their usefulness for specifically interrogating PAR2 in vivo. Structure-activity relationships were used to derive new PAR2 agonists and antagonists containing nonpeptidic moieties. Agonist GB110 (19, EC(50) 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca(2+) release in HT29 human colorectal carcinoma cells. Antagonist GB83 (36, IC(50) 2 μM) is the first compound at micromolar concentrations to reversibly inhibit PAR2 activation by both proteases and other PAR2 agonists (e.g., trypsin, 2f-furoyl-LIGRLO-NH(2), 19). The new compounds are selective for PAR2 over PAR1, serum stable, and suitable for modulating PAR2 in disease models.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barry
authors.forename: Jacky Y
authors.initials: JY
authors.lastname: Suen
authors.forename: Giang T
authors.initials: GT
authors.lastname: Le
authors.forename: Adam
authors.initials: A
authors.lastname: Cotterell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D044967:Serum
chemical_list: C553267:5-isoxazoyl-cyclohexylalanyl-isoleucyl-(3-(aminomethyl)phenyl)-(4-(aminomethyl)piperidin-1-yl)methanone; C553268:5-isoxazoyl-cyclohexylalanyl-isoleucyl-spiroindane-1,4'-piperidine; D004151:Dipeptides; D007555:Isoxazoles; D009842:Oligopeptides; D044464:Receptor, PAR-2; D002118:Calcium