Functional studies cast light on receptor states

Contemporary analysis of the functional responses of G-protein-coupled receptors (GPCRs) usually addresses drug-receptor interactions from the perspective of the average behavior of the receptor population. This behavior is characterized in terms of observed affinity and efficacy. Efficacy is a measure of how well a drug activates the receptor population and observed affinity a measure of how potently a drug occupies the receptor population. The latter is quantified in terms of the dissociation constant of the ligand-receptor complex. At a deeper level of analysis, drug-receptor interactions are described in terms of ligand affinity constants for active and inactive receptor states. Unlike observed affinity and efficacy, estimates of receptor state affinity constants are unperturbed by G proteins, guanine nucleotides, or other signaling proteins that interact with the receptor. Recent advances in the analysis of the functional responses of GPCRs have enabled the estimation of receptor state affinity constants. These constants provide a more fundamental measure of drug-receptor interactions and are useful in analyzing structure-activity relationships and in quantifying allosterism, biased signaling, and receptor-subtype selectivity.