Abstract
G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi-response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins.
Highlights
When two dose-dependent receptor functional response curves are compared, the conventional midpoint EC50 or IC50 values may not mean equal response, even though they are at half of each curve’s own maximal window of response
Rather than resorting to tedious graphical interpolations of pairwise curves to arrive at a finite number of selectivity values, we calculate a continuous, panoramic equi-response and equi-occupancy selectivity space from all parameters measured in dose-dependent receptor agonism and allosterism assays
Since receptor alloterism dose response curves are dependent on both agonist and modulator concentrations as well as affinity and efficacy parameters, equi-response selectivity is dependent on the dose combination matrix and all parameters
Summary
When two dose-dependent receptor functional response curves are compared, the conventional midpoint EC50 or IC50 (or any ECx or ICx) values may not mean equal response, even though they are at half (or x%) of each curve’s own maximal window of response. In all of the above cases, the midpoint EC50 or IC50 or ECx or ICx value for each curve can mean a different relative level of response To address this conundrum of comparison at unequal receptor functional response or occupancy and to develop both dose- and all parameters-dependent selectivity measure that is broader and more general than agonist bias, we apply the concept of null (equal response) method to the dose-response curves in receptor agonism and allosterism. It provides a comprehensive way of comparing head to head two agonists, modulators, receptors or signaling pathways This measure of selectivity based on a hitherto unpublished set of equations relating two sets of all relevant parameters represents a new development in quantitative receptor pharmacology. It has the advantage of capturing the nonobvious, subtle and/or substantial impact of all agonism and allosterism parameters in the context of fluctuating concentrations of agonist and modulator, potentially enabling predictive or translational pharmacokinetics-pharmacodynamics
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