Agonists and Antagonists of Protease Activated Receptors (PARs)

Abstract

Protease activated receptors (PARs) are a category of G-protein coupled receptors (GPCRs) implicated in the progression of a wide range of diseases, including thrombosis, inflammatory disorders, and proliferative diseases. Signal transduction via PARs proceeds via an unusual activation mechanism. Instead of being activated through direct interaction with an extracellular signal like most GPCRs, they are self-activated following cleavage of their extracellular N-terminus by serine proteases to generate a new receptor N-terminus that acts as an intramolecular ligand by folding back onto itself and triggering receptor activation. Short synthetic peptides corresponding to this newly exposed N-terminal tethered ligand can activate three of the four known PARs in the absence of proteases, and such PAR activating peptides (PAR-APs) have served as templates for agonist/antagonist development. In fact much of the evidence for involvement of PARs in diseases has relied upon use of PAR-APs, often of low potency and uncertain selectivity. This review summarizes current structures of PAR agonists and antagonists, the need for more selective and more potent PAR ligands that activate or antagonize this intriguing class of receptors, and outlines the background relevant to PAR activation, assay methods, and physiological properties anticipated for PAR ligands.

Osteosarcoma cell‐calcium signaling through tissue factor–factor VIIa complex and factor Xa

“…Thus, further experiments dealing with, for example, purified primary cultured human osteoblasts, are needed. Recent developments indicate that TF, when bound to FVIIa, is involved in cell signaling, especially through PAR-2 activation [2]. In this paper, we showed that, in an osteoblastic-like cell line, TF is expressed and acts as a signaling factor.…”

“…Thrombin digests fibrinogen into fibrin monomers [1]. TF is expressed in non-circulating and circulating cells [2], as well as organs [3]. Recently, an alternatively spliced tissue factor (asTF), consisting only of the extracellular sequence, was identified in humans and mice [4].…”

Benzylamide antagonists of protease activated receptor 2 with anti-inflammatory activity

“…16 Compound 1 is unstable in vivo due to proteolysis, but the non-peptidic agonist 2 is a promising template for elaborating to a plasma stable PAR2 antagonist. We previously reported that replacement of the C-terminal primary amine in 2 with a morpholine group produced a weak antagonist (3,IC 50 Structure-activity relationship (SAR) studies on the PAR2 antagonist GB88 (4) suggested that the isoxazolyl, cyclohexyl-alanine and isoleucine residues were intolerant of other substitution for antagonist potency (unpublished results). Our PAR2 homology model (derived from ORL-1 receptor crystal structure 4EA3)…”

“…[1][2][3][4] PAR2 is expressed in immune and inflammatory cells including T-cells, monocytes, macrophages as well as in many types of cancer cells. [3][4][5][6] There has been some controversy about PAR2 activation being pro-and/or anti-inflammatory.…”

“…[1][2][3][4] PAR2 is expressed in immune and inflammatory cells including T-cells, monocytes, macrophages as well as in many types of cancer cells. [3][4][5][6] There has been some controversy about PAR2 activation being pro-and/or anti-inflammatory. 4,7 However PAR2 activation is clearly associated with inflammatory diseases such as arthritis [8][9] and inflammatory bowel disease, [10][11][12] stimulating growth and invasion of pro-inflammatory and cancer cells, producing TNF-α and IL-6, and inducing joint swelling, mechanical and thermal hyper-algesia.…”