Selected Biased Antagonists Include Compound 562 Essay examples

1447 Words Nov 3rd, 2016 6 Pages
Selected biased antagonists include compound 562 (C562; 2at-SKGRS-PEG3-Hdc) and compound 608 (C608; 2at-TIGR-PEG3-Hdc). Both C562 and C608 effectively block protease activated, PAR2-mediated Ca2+ signaling (Figure 8) without blocking of MAPK signaling. Based on preliminary data, C562 will initially be used at 5 M concentrations and C608 at 500 nM. C608 is a unique compound in that at high concentrations (>1 M) it is a partial, biased (Ca2+-signaling only) agonist, and a full MAPK agonist at very high concentrations (EC50 = 20 M). Thus, in addition to using C608 as a biased antagonist, we can use this compound at succesfully higher concentrations to partially activate PAR2-dependent Ca2+ signaling independent of -arrestin/MAPK signaling, or, to partially activate Ca2+ signaling and fully activate MAPK signaling. The available combinations of high potency agonists and antagonists, and, concentration dependent mixed signaling antagonists will allow for initial evaluation of biased signaling responses (Table 1). Our separate PAR2 drug discovery efforts are ongoing and independently funded. Should more appropriate compounds (e.g., increased potency/efficacy; altered biased agonism/antagonism) be discovered they will be immediately available for the allergic asthma studies described below. In C562 and C608 we have unique PAR2 modulators that can be used to begin to tease out the effects of biased PAR2 signaling in asthma models. When appropriate, we will use these and other unique…

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