title: PAR2 Modulators Derived from GB88.
abstract: PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining affinity and selectivity, while the C-terminal substituent determines agonist/antagonist function. Here we report structurally similar PAR2 ligands with opposing functions (agonist vs antagonist) upon binding to PAR2. A biased ligand AY117 (65) was found to antagonize calcium release induced by PAR2 agonists trypsin and hexapeptide 2f-LIGRLO-NH2(IC502.2 and 0.7 μM, HT29 cells), but it was a selective PAR2 agonist in inhibiting cAMP stimulation and activating ERK1/2 phosphorylation. It showed anti-inflammatory properties bothin vitroandin vivo.
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Mei-Kwan
authors.initials: MK
authors.lastname: Yau
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Jacky Y
authors.initials: JY
authors.lastname: Suen
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Rink-Jan
authors.initials: RJ
authors.lastname: Lohman
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Cotterell
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barry
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Jeffrey Y W
authors.initials: JY
authors.lastname: Mak
authors.affiliation: Centre for Kidney Research, Department of Medicine, The University of Queensland, Princess Alexandra Hospital , Brisbane, Queensland 4102, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Vesey
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.affiliation: Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
keywords: Protease activated receptor 2 (PAR2); agonist; antagonist; inflammation; structure−activity relationship (SAR)