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PAR2 Modulators Derived from GB88.

Mei-Kwan Yau1, Ligong Liu1, Jacky Y Suen1

  • 1Division 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.

ACS Medicinal Chemistry Letters
|December 21, 2016
PubMed
Summary
This summary is machine-generated.

New biased PAR2 ligands show opposing functions, acting as antagonists for calcium release but agonists for anti-inflammatory effects. This discovery offers potential for treating various inflammatory and metabolic disorders.

Keywords:
Protease activated receptor 2 (PAR2)agonistantagonistinflammationstructure−activity relationship (SAR)

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Protease-activated receptor 2 (PAR2) is a target for inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders.
  • Few PAR2 antagonists are currently known, limiting therapeutic options.

Purpose of the Study:

  • To identify and characterize novel PAR2 ligands with opposing agonist and antagonist functions.
  • To investigate the potential of these biased ligands in treating inflammatory conditions.

Main Methods:

  • Synthesis and characterization of structurally similar PAR2 ligands.
  • Assessment of ligand function (agonist/antagonist) on calcium release, cAMP inhibition, and ERK1/2 phosphorylation in HT29 cells.
  • Evaluation of anti-inflammatory properties in vitro and in vivo.

Main Results:

  • A biased ligand, AY117, selectively antagonized PAR2-mediated calcium release (IC50 values of 2.2 and 0.7 μM).
  • AY117 acted as a selective PAR2 agonist, inhibiting cAMP stimulation and activating ERK1/2 phosphorylation.
  • AY117 demonstrated anti-inflammatory properties in both in vitro and in vivo models.

Conclusions:

  • Structurally similar PAR2 ligands can exhibit opposing functional outcomes (agonist vs. antagonist).
  • Biased PAR2 ligands like AY117 offer a promising therapeutic strategy for inflammatory diseases.
  • Targeting PAR2 with biased ligands warrants further investigation for various metabolic and inflammatory conditions.