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Vol. 299, Issue 1, 323-331, October 2001

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

Edward F. Nemeth, Eric G. Delmar, William L. Heaton, Michael A. Miller, Lyssa D. Lambert, Rebecca L. Conklin, Maxine Gowen, John G. Gleason, Pradip K. Bhatnagar and John Fox

NPS Pharmaceuticals, Inc., Salt Lake City, Utah (E.F.N., E.G.D., W.L.H., M.A.M., L.D.L., R.L.C., J.F.); and Departments of Bone and Cartilage Biology (M.G.) and Medicinal Chemistry (J.G.G., P.K.B.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania

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+]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. 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.

0022-3565/01/2991-0323$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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