Biasing the parathyroid hormone receptor: relating in vitro ligand efficacy to in vivo biological activity.

Recent advances in our understanding of the pluridimensional nature of GPCR signaling have provided new insights into how orthosteric ligands regulate receptors, and how the phenomenon of functional selectivity or ligand "bias" might be exploited in pharmaceutical design. In contrast to the predictions of simple two-state models of GPCR function, where ligands affect all aspects of GPCR signaling proportionally, current models assume that receptors exist in multiple "active" conformations that differ in their ability to couple to different downstream effectors, and that structurally distinct ligands can bias signaling by preferentially stabilizing different active states. The type 1 parathyroid hormone receptor (PTH(1)R) offers unique insight into both the opportunities and challenges of exploiting ligand bias in pharmaceutical design, not only because numerous "biased" PTH analogs have been described but also because many of them have been characterized for biological activity in vivo.