Protease activated receptor-1 (PAR-1) is a G-coupled receptor cleaved by thrombin and other proteases to expose a new N-terminus, a “tethered ligand”, that activates the receptor. Independently of proteolytic cleavage, peptides similar to the new N-terminus also activate the receptor, and structure activity relationships for the activating peptides have been extensively studied. Modification of activating peptides led to rationally designed peptide antagonists. The more potent peptide antagonists were N-terminal and 3-position modifications of the agonist peptides. The resulting PAR- 1 antagonists have proved useful in pharmacological studies resolving the contribution of PAR-1 signaling mechanisms relative to other PARs in platelets, vascular endothelial and other cell types. High affinity peptide agonists and antagonists have been radiolabled and proven useful in binding assays. Screening of combinatorial libraries and compound collections using the radioligands have identified non-peptide antagonists of several different chemotypes. When the “thrombin receptor” (PAR-1) was first cloned and its mechanism of activation elucidated, there was great enthusiasm for the receptor as a drug target. The use of peptide agonists and antagonists has made possible much progress in our understanding of the role of this receptor.
Keywords: protease activated receptor, par, thrombin receptor, thrombin receptor antagonist, thrombosis, coupled receptor
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