Calcilytic Compounds: Potent and Selective Ca2+Receptor Antagonists That Stimulate Secretion of Parathyroid Hormone

Despite the discovery of many ions and molecules that activate the Ca 2+ receptor, there are no known ligands that block this receptor. Reported here are the pharmacodynamic properties of a small molecule, NPS 2143, which acts as an antagonist at the Ca 2+ receptor. This compound blocked (IC 50 of 43 nM) increases in cytoplasmic Ca 2+ concentrations [Ca 2+ ] i elicited by activating the Ca 2+ receptor in HEK 293 cells expressing the human Ca 2+ receptor. NPS 2143, even when tested at much higher concentrations (3 μM), did not affect the activity of a number of other G protein-coupled receptors, including those most structurally homologous to the Ca 2+ receptor. NPS 2143 stimulated parathyroid hormone (PTH) secretion from bovine parathyroid cells (EC 50 of 41 nM) over a range of extracellular Ca 2+ concentrations and reversed the effects of the calcimimetic compound NPS R-467 on [Ca 2+ ] i and on secretion of PTH. When infused intravenously in normal rats, NPS 2143 caused a rapid and large increase in plasma levels of PTH. Ca 2+ receptor antagonists are termed calcilytics and NPS 2143 is the first substance (either atomic or molecular) shown to possess such activity. The pharmacodynamic properties of NPS 2143 together with the recently demonstrated effects of this compound on bone formation support the view that orally active calcilytic compounds might provide a novel anabolic therapy for osteoporosis.