Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi-Occupancy Selectivity.
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.
Merck Research Laboratories, Department of In Vitro Pharmacology, Kenilworth, New Jersey, USA.
Rumin
R
Zhang
Merck Research Laboratories, Department of In Vitro Pharmacology, Kenilworth, New Jersey, USA.
Michael
M
Kavana
D000465:Algorithms; D000494:Allosteric Regulation; D000818:Animals; D015195:Drug Design; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
D043562:Receptors, G-Protein-Coupled