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 Ca2+ rec eptor, there are no known ligands that block this receptor. Reported here a re the pharmacodynamic properties of a small molecule, NIPS 2143, which act s as an antagonist at the Ca2+ receptor. This compound blocked (IC50 of 43 nM) increases in cytoplasmic Ca2+ concentrations [Ca2+](i) elicited by acti vating the Ca2+ receptor in HEK 293 cells expressing the human Ca2+ recepto r. NPS 2143, even when tested at much higher concentrations (3 muM), did no t affect the activity of a number of other G protein-coupled receptors, inc luding those most structurally homologous to the Ca2+ receptor. NIPS 2143 s timulated parathyroid hormone (PTH) secretion from bovine parathyroid cells (EC50 of 41 nM) over a range of extracellular Ca2+ concentrations and reve rsed the effects of the calcimimetic compound NPS R-467 on [Ca2+](i) and on secretion of PTH. When infused intravenously in normal rats, NPS 2143 caus ed a rapid and large increase in plasma levels of PTH. Ca2+ receptor antago nists are termed calcilytics and NPS 2143 is the first substance (either at omic or molecular) shown to possess such activity. The pharmacodynamic prop erties of NIPS 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.