The potential for selective pharmacological therapies through biased receptor signaling

Agonists constitute a major class of therapeutic drug and pose special problems with respect to the drug discovery process. Specifically, agonist activity is intimately tied to the sensitivity of the tissue in which the activity is measured therefore the obvious measures of agonist activity (i.e. potency and maximal response) can be complex and certainly are system dependent. As in most cases, new therapeutic entities are discovered, optimized and characterized in test systems, rarely the therapeutic one. Therefore, system-independent reliable scales to describe agonist activity are critical in the process of identifying agonist drug candidates. A pharmacologic workhorse for the quantification of agonist activity has been the agonist potency ratio. This tool compares equal responses via null methods to cancel tissue effects to yield ratios that depend only on agonist affinity and efficacy. Since these are unique properties of the molecules, these ratios can be system independent and invaluable as predictors of activity in therapeutic systems. Potency ratios are applicable only when comparing full agonists and cannot be applied to comparisons of full to partial agonist activity. However, other techniques that identify system independent measures of agonist activity can be estimated through tools such as the Black/Leff operational model; this characterizes the affinity (as KA-1 where KA is the equilibrium dissociation constant of the agonist-receptor complex) and τ (where τ is the agonist intrinsic efficacy and sensitivity to agonist of the tissue- vide infra) [1]. Thus estimates of τ and KA become the system independent measures of agonism.The use of these techniques to compare whole cell activity for drug discovery depends on an important assumption, namely that the function linking receptor occupancy and tissue response be monotonic (i.e. that there be only one value of y (response) for every x (concentration of drug)). Under these circumstances, ratios of activity