Abstract

Despite the discovery of many ions and molecules that activate the Ca²⁺ 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 Ca²⁺receptor. This compound blocked (IC₅₀ of 43 nM) increases in cytoplasmic Ca²⁺ concentrations [Ca²⁺]_i elicited by activating the Ca²⁺ receptor in HEK 293 cells expressing the human Ca²⁺ 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 Ca²⁺ receptor. NPS 2143 stimulated parathyroid hormone (PTH) secretion from bovine parathyroid cells (EC₅₀ of 41 nM) over a range of extracellular Ca²⁺ concentrations and reversed the effects of the calcimimetic compound NPS R-467 on [Ca²⁺]_iand on secretion of PTH. When infused intravenously in normal rats, NPS 2143 caused a rapid and large increase in plasma levels of PTH. Ca²⁺ 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.