Recent advances in the understanding of G-protein coupled receptor (GPCR) pharmacology have demonstrated that certain ligands can selectively engage different GPCR-mediated signaling pathways. This phenomenon, called biased signaling, has been demonstrated with protease-activated receptors (PARs), a unique subset of GPCRs with profound effects on diverse phenomena such as platelet activation, inflammation, and cancer cell metastasis. We previously discovered a class of small molecules, called parmodulins, that act to selectively inhibit platelet granule secretion via PAR1-activated Gq. Presented here is a selection of our efforts to 1) identify analogs with improved properties using medicinal chemistry; 2) characterize the promising cytoprotective effects of these compounds; 3) synthesize first-in-class bivalent ligands.

Strategies for the modulation of protease-activated receptors (PARs)

254th National Meeting (2017)

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