Introduction. R-Thrombin is a key trypsin-like serine protease involved in coagulation and a variety of cellular actions, such as platelet aggregation, lymphocyte mitosis, monocyte chemotaxis, and endothelial cell proliferation. 1-4 Many of the effects of thrombin on cells are mediated by specific cell-surface receptors, which eluded identification for many years. However, in 1991, Coughlin and co-workers identified the first example of a thrombin receptor (protease-activated receptor-1, PAR-1), a member of the vast superfamily of seven-transmembrane, G-protein-coupled receptors. 5 Thrombin proteolytically cleaves the lengthy N-terminal extracellular domain of PAR-1 at the Arg-41/Ser-42 peptide bond to unveil a new N-terminus containing the recognition sequence SFLLRN, which appears to serve as a “tethered” peptide ligand. Interestingly, synthetic peptides containing this epitope exhibit full PAR-1 agonist activity, 6 and extensive structure-function data have been accumulated. 6-9 Three additional PARs, PAR-2, 10 PAR-3, 11 and PAR-4, 12 which are homologous to PAR-1, are now known, and each has its own agonist peptide motif.

PAR-1 mediates most of the cellular actions of thrombin, such as platelet aggregation, cell proliferation, inflammatory responses, and neurodegeneration. Thus, this receptor is an attractive drug discovery target for the possible treatment of various disorders such as thrombosis, restenosis, atherosclerosis, inflammation, cancer metastasis, and stroke. 2, 13-15 Conceivably, a PAR-1 antagonist would be able to interfere with the cellular actions of thrombin without impacting on thrombin’s role in coagulation and hemostasis. Additionally, a PAR-1 antagonist would provide a useful pharmacological tool for characterizing the physiological role of PAR-1, which has yet to be clearly delineated.