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*Compound via MeSH
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Hazardous Substances DB
*CALCITONIN, SALMON
*CALCIUM COMPOUNDS
*CALCIUM, ELEMENTAL
*PARATHYROID HORMONE

Vol. 290, Issue 2, 473-479, August 1999

NPS R-568: A Type II Calcimimetic Compound that Acts on Parathyroid Cell Calcium Receptor of Rats to Reduce Plasma Levels of Parathyroid Hormone and Calcium

John Fox, Stacey H. Lowe, Barbara A. Petty and Edward F. Nemeth

NPS Pharmaceuticals, Inc., Salt Lake City, Utah

Calcimimetics like N-(3-[2-chlorophenyl]propyl)-(R)-alpha -methyl-3-methoxybenzylamine (NPS R-568) potentiate the effects of extracellular Ca2+ on parathyroid Ca2+ receptors and inhibit parathyroid hormone (PTH) secretion in vitro. When administered by gavage to normal rats in this study, NPS R-568 caused a rapid, dose-dependent (ED50, 1.1 ± 0.7 mg/kg) decrease in PTH levels that was paralleled by a subsequent decrease in plasma Ca2+ (ED50, 10.4 ± 3.7 mg/kg). At higher doses (>= 3.3 mg/kg), PTH was reduced to a minimum level within 15 min, the duration of which was dose dependent. With doses of 10 to 100 mg/kg, the hypocalcemia was rapid in onset (<30 min) and, at 33 to 100 mg/kg, persisted for >24 h. Neither the magnitude nor the kinetics of the hypocalcemic response was affected by total nephrectomy, demonstrating that NPS R-568 does not induce hypocalcemia by acting on renal Ca2+ receptors to increase Ca2+ excretion. In contrast, parathyroidectomy (intact thyroid) abolished the hypocalcemic response to NPS R-568, regardless of whether the rats were hypocalcemic or rendered acutely normo- or hypercalcemic by calcium infusion before dosing. These data show that the parathyroid Ca2+ receptor can be selectively activated in vivo with a small organic compound to decrease plasma levels of PTH and Ca2+ and thus define the mechanism of action of this compound in vivo. Moreover, the data add pharmacological support to the view that the Ca2+ receptor is the primary molecular entity regulating systemic Ca2+ homeostasis.

0022-3565/99/2902-0473$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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