Collateral efficacy as a pharmacological problem applied to new drug discovery

Before the direct measurement of G-protein-coupled receptor (GPCR) behaviour was possible, all GPCR ligand efficacy was assumed to be linear, that is, to emanate only from physiological activation of the receptor as observed through tissue response. Subsequent advances in technology have enabled the observation of the effects unrelated to GPCR response (e.g., receptor phosphorylation and internalisation), as well as separate response pathways independent of G protein activation (i.e., β-arrestin extracellular signal-related kinase [ERK1/2] activation). These increased vantage points have revealed ligands that have efficacies for some, but not all, GPCR behaviours; this is referred to as collateral efficacy. These ideas are explored, with examples, in the context of possibly more focused therapeutic application of agonists and antagonists.