IBMS BoneKEy | Perspective

Mimetic ligands for the PTHR1: Approaches, developments, and considerations

Thomas J Gardella

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DOI:10.1138/20090364

Abstract

The peptide ligands PTH and PTHrP can robustly stimulate new bone formation via agonist actions on the PTH/PTHrP receptor (PTHR1). Thus there is considerable interest in finding orally active small-molecule ligands for this target receptor, but so far no potent mimetic agonist has been described. Several small-molecule ligands that show either antagonistic or weak agonistic activities on the PTHR1 have recently appeared in the literature. These compounds represent potential leads for further chemical development. Advances made in our understanding of the molecular processes by which PTH and PTHrP peptide ligands and their analogs bind to and activate the PTHR1 are likely to be relevant to the mechanisms of action used by any PTHR1 mimetic ligand. This article aims to place these recent findings in a context that helps illuminate the challenges posed by the PTH/PTHrP receptor, and perhaps suggest new paths to take for the eventual development of potent and orally active mimetic agonists for this medically and biologically important G protein-coupled receptor.

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