Potent Small Agonists of Protease Activated Receptor 2.

Many proteases cut the PAR2 N-terminus resulting in conformational changes that activate cells. Synthetic peptides corresponding to newly exposed N-terminal sequences of PAR2 also activate the receptor at micromolar concentrations. PAR2-selective small molecules reported here induce PAR2-mediated intracellular calcium signaling at nanomolar concentrations (EC50 = 15-100 nM, iCa(2+), CHO-hPAR2 cells). These are the most potent and efficient small molecule ligands to activate PAR2-mediated calcium release and chemotaxis, including for human breast and prostate cancer cells.