Endocrine Abstracts (2001) 2 SP20

Calcium Receptor Antagonists

EF Nemeth


NPS Pharmaceuticals, Toronto, Ontario, Canada.


The cell surface calcium receptor is the primary molecular entity regulating secretion of parathyroid hormone (PTH). Activation of this receptor by extracellular calcium inhibits PTH secretion whereas blocking the calcium receptor stimulates secretion of PTH. Chronically elevated levels of PTH, as occurs in hyperparathyroidism, stimulate bone resorption whereas temporary increases in circulating levels of PTH stimulate bone formation. This stimulatory effect on bone has prompted development of exogenous PTH or its N-terminal peptide fragment as novel anabolic therapies for osteoporosis. An alternative approach is based on the use of small, orally active compounds which block the calcium receptor thereby increasing the circulating levels of endogenous PTH. Compounds acting as antagonists of the calcium receptor are termed calcilyticsand the prototype compound is NPS 2143. This small organic compound inhibits (IC50 = 43 nM) the activity of the human parathyroid cell Ca2+ receptor in HEK 293 cells but is without effect on a number of structurally homologous G protein-coupled receptors. NPS 2143 stimulates secretion of PTH from bovine parathyroid cells in vitro (EC50 = 41 nM). Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats results in a sustained increase in plasma PTH levels causing a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent administration of NPS 2143 and 17beta-estradiol also increases bone turnover. However, the antiresorptive action of estrogen decreases the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyroid gland, parathyroid cells did not undergo hyperplasia. Calcilytic compounds with improved pharmacokinetic properties might be used to temporarily increase circulating levels of PTH and thereby stimulate new bone formation in osteoporotic patients.

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