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

Calcimimetics like N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxyb enzylamine (NPS R-568) potentiate the effects of extracellular Ca2+ on para thyroid Ca2+ receptors and inhibit parathyroid hormone (PTH) secretion in v itro. When administered by gavage to normal rats in this study, NPS R-568 c aused a rapid, dose-dependent (ED50, 1.1 +/- 0.7 mg/kg) decrease in PTH lev els that was paralleled by a subsequent decrease in plasma Ca2+ (ED50, 10.4 +/- 3.7 mg/kg). At higher doses (greater than or equal to 3.3 mg/kg), PTH was reduced to a minimum level within 15 min, the duration of which was dos e dependent. With doses of 10 to 100 mg/kg, the hypocalcemia was rapid in o nset (<30 min) and, at 33 to 100 mg/kg, persisted for >24 h. Neither the ma gnitude 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, par athyroidectomy (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 electively activated in vivo wit h a small organic compound to decrease plasma levels of PTH and Ca2+ and th us define the mechanism of action of this compound in vivo. Moreover, the d ata add pharmacological support to the view that the Ca2+ receptor is the p rimary molecular entity regulating systemic Ca2+ homeostasis.