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Vol. 290, Issue 2, 480-486, August 1999

Calcimimetic Compound NPS R-568 Stimulates Calcitonin Secretion But Selectively Targets Parathyroid Gland Ca2+ Receptor in Rats

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

NPS Pharmaceuticals, Inc., Salt Lake City, Utah

N-(3-[2-Chlorophenyl]propyl)-(R)-alpha -methyl-3-methoxybenzylamine (NPS R-568) is an orally active compound that activates Ca2+ receptors on parathyroid cells and rapidly suppresses plasma levels of parathyroid hormone (PTH) and Ca2+ (ED50, 1 and 10 mg/kg, respectively). We now show that increased calcitonin secretion contributes to NPS R-568-induced hypocalcemia. In parathyroidectomized thyroid-intact rats in which normocalcemia was restored by PTH infusion, NPS R-568 rapidly reduced plasma Ca2+ levels, indicating that decreased PTH secretion was not solely responsible for the hypocalcemia seen in normal animals. NPS R-568 decreased plasma Ca2+ levels in thyroidectomized parathyroid-intact rats, but the rate of onset of hypocalcemia was slower than in controls. In contrast, NPS R-568 had no effect on plasma Ca2+ levels in PTH-infused, thyroparathyroidectomized rats, providing evidence that increased calcitonin secretion caused the hypocalcemia in PTH-infused parathyroidectomized rats. NPS R-568 rapidly increased plasma calcitonin levels to a peak at 10 to 20 min after oral dosing (ED50 40 mg/kg). NPS R-568 did not affect the rate of disappearance of 45Ca from blood, indicating that hypocalcemia resulted from decreased influx of Ca2+ into the circulation and not from increased efflux. This suggests that NPS R-568-induced hypocalcemia resulted solely from reduced efflux of Ca2+ from bone after increased calcitonin and reduced PTH secretion. Thus, NPS R-568 causes hypocalcemia by activating Ca2+ receptors on C cells and parathyroid cells; however, NPS R-568 is about 40 times more potent in reducing PTH levels than in increasing calcitonin levels.

0022-3565/99/2902-0480$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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