'Functional selectivity' refers to the ability of a
ligand to activate and/or inhibit only a subset of the signals capable of emanating from its cognate
G-protein-coupled receptor (GPCR). Whereas conventional GPCR agonism and antagonism can be viewed as modulating the quantity of efficacy, functionally selective or 'biased'
ligands qualitatively change the nature of information flow across the plasma membrane, raising the prospect of drugs with improved therapeutic efficacy or reduced side effects. Nonetheless, there is little experimental evidence that biased
ligands offer advantages over conventional agonists/antagonists in vivo. Recent work with the type I
parathyroid hormone receptor (PTH(1) R) suggests that biased
ligands that selectively activate
G-protein-independent
arrestin-mediated signalling pathways may hold promise in the treatment of
osteoporosis.
Parathyroid hormone (PTH) is a principle regulator of bone and
calcium metabolism. In bone, PTH exerts complex effects; promoting new bone formation through direct actions on osteoblasts while simultaneously stimulating bone loss through indirect activation of osteoclastic
bone resorption. Although the conventional PTH(1) R agonist
teriparatide,
PTH(1-34), is effective in the treatment of
osteoporosis, its utility is limited by its bone-resorptive effects and propensity to promote hypercalcaemia/hypercalcuria. In contrast, d-Trp(12) ,Tyr(34) -bPTH(7-34) (PTH-βarr), an
arrestin pathway-selective agonist for the PTH(1) R, induces anabolic bone formation independent of classic
G-protein-coupled signalling mechanisms. Unlike
PTH(1-34), PTH-βarr appears to 'uncouple' the
anabolic effects of PTH(1) R activation from its catabolic and calcitropic effects. Such findings offer evidence that
arrestin pathway-selective GPCR agonists can elicit potentially beneficial effects in vivo that cannot be achieved using conventional agonist or antagonist
ligands.