title: Potent agonists of the protease activated receptor 2 (PAR2).
abstract: Novel peptidomimetic pharmacophores to PAR(2) were designed based on the known activating peptide SLIGRL-NH(2). A set of 15 analogues was evaluated with a model cell line (16HBE14o-) that highly expresses PAR(2). Cells exposed to the PAR(2) activating peptide with N-terminal 2-furoyl modification (2-furoyl-LIGRLO-NH(2)) initiated increases in intracellular calcium concentration ([Ca(2+)](i) EC(50) = 0.84 μM) and in vitro physiological responses as measured by the xCELLigence real time cell analyzer (RTCA EC(50) = 138 nM). We discovered two selective PAR(2) agonists with comparable potency: compound 1 (2-aminothiazol-4-yl; Ca(2+) EC(50) = 1.77 μM, RTCA EC(50) = 142 nM) and compound 2 (6-aminonicotinyl; Ca(2+) EC(50) = 2.60 μM, RTCA EC(50) = 311 nM). Unlike the previously described agonist, these novel agonists are devoid of the metabolically unstable 2-furoyl modification and thus provide potential advantages for PAR(2) peptide design for in vitro and in vivo studies. The novel compounds described herein also serve as a starting point for structure-activity relationship (SAR) design and are, for the first time, evaluated via a unique high throughput in vitro physiological assay. Together these will lead to discovery of more potent agonists and antagonists of PAR(2).
authors.affiliation: Arizona Respiratory Center and Department of Physiology, University of Arizona, 1501 N Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Boitano
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Flynn
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Schulz
authors.forename: Justin
authors.initials: J
authors.lastname: Hoffman
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.forename: Josef
authors.initials: J
authors.lastname: Vagner
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D009842:Oligopeptides; D057786:Peptidomimetics; D044464:Receptor, PAR-2; D013844:Thiazoles; D002118:Calcium