Being mindful of seven-transmembrane receptor 'guests' when assessing agonist selectivity

Abstract

The time-honored approach of quantifying agonist selectivity through measurement of agonist affinity with binding and efficacy through potency ratios in model assays for prediction of effect in therapeutic systems can fall short of providing useful answers for functionally selective agonists. Agonists are now known to have pluridimensional efficacies that are associated with selected signalling pathways coupled to the receptor. This necessitates specifically tailored assay formats to measure pre-determined efficacies of ligands to characterize agonist selectivity fully. If such assays can access signalling that directly emanates from the interaction of the agonist-bound receptor and a cytosolic signalling protein, then the Black/Leff operational model can be used to specifically quantify 'transduction ratios' (tau/K(A)) that fully characterize selective activation of signalling pathways by a given agonist. As whole-cell processing of pleiotropic signalling cascades imposes cell-specific phenotypic agonist profiles, ultimately the assessment of agonist selectivity is most reliably done in the therapeutically relevant primary cell system.

Figure 1

Classical allosteric system for 7TMR agonism. All agonists become the ‘modulator’, the receptor is the ‘conduit’ and the cytosolic signalling molecules are the ‘guests’. Within this scheme, the Black/Leff operational model can be used to quantify selective activation of pathways through identification of unique log(τ/K_A) ratios.