Refining efficacy: exploiting functional selectivity for drug discovery

Early models of G protein-coupled receptor (GPCR) activation envisioned the receptor in equilibrium between unique "off" and "on" states, wherein ligand binding affected signaling by increasing or decreasing the fraction of receptors in the active conformation. It is now apparent that GPCRs spontaneously sample multiple conformations, any number of which may couple to one or more downstream effectors. Such "multistate" models imply that the receptor-ligand complex, not the receptor alone, defines which active receptor conformations predominate. "Functional selectivity" refers to the ability of a ligand to activate only a subset of its receptor's signaling repertoire. There are now numerous examples of ligands that "bias" receptor coupling between different G protein pools and non-G protein effectors such as arrestins. The type 1 parathyroid hormone receptor (PTH(1)R) is a particularly informative example, not only because of the range of biased effects that have been produced, but also because the actions of many of these ligands have been characterized in vivo. Biased PTH(1)R ligands can selectively couple the PTH(1)R to G(s) or G(q/11) pathways, with or without activating arrestin-dependent receptor desensitization and signaling. These reagents have provided insight into the contribution of different signaling pathways to PTH action in vivo and suggest it may be possible to exploit ligand bias to uncouple the anabolic effects of PTH(1)R from its catabolic and calcitropic effects. Whereas conventional agonists and antagonists only modulate the quantity of efficacy, functionally selective ligands qualitatively change GPCR signaling, offering the prospect of drugs with improved therapeutic efficacy or reduced side effects.