PT - JOURNAL ARTICLE AU - John Fox AU - Stacey H. Lowe AU - Barbara A. Petty AU - Edward F. Nemeth TI - 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 DP - 1999 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 473--479 VI - 290 IP - 2 4099 - http://jpet.aspetjournals.org/content/290/2/473.short 4100 - http://jpet.aspetjournals.org/content/290/2/473.full SO - J Pharmacol Exp Ther1999 Aug 01; 290 AB - Calcimimetics likeN-(3-[2-chlorophenyl]propyl)-(R)-α-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. The American Society for Pharmacology and Experimental Therapeutics