'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.
Published 2011. This article is a U.S. Government work and is in the public domain in the USA.