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-methoxybenzylamine (NPS R-568) potentiate the effects of extracellular Ca(2+) on parathyroid Ca(2+) 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 (ED(50), 1.1 +/- 0.7 mg/kg) decrease in PTH levels that was paralleled by a subsequent decrease in plasma Ca(2+) (ED(50), 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 Ca(2+) receptors to increase Ca(2+) 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 Ca(2+) receptor can be selectively activated in vivo with a small organic compound to decrease plasma levels of PTH and Ca(2+) and thus define the mechanism of action of this compound in vivo. Moreover, the data add pharmacological support to the view that the Ca(2+) receptor is the primary molecular entity regulating systemic Ca(2+) homeostasis.
NPS Pharmaceuticals, Inc., Salt Lake City, Utah. jfox@npsp.com
J
J
Fox
S H
SH
Lowe
B A
BA
Petty
E F
EF
Nemeth
D000814:Aniline Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D002116:Calcitonin / Q000097:blood; D002118:Calcium / Q000097:blood*; D002135:Calcium-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D008297:Male; D009392:Nephrectomy; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood*; D016105:Parathyroidectomy; D010627:Phenethylamines; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley
D000814:Aniline Compounds; D002135:Calcium-Binding Proteins; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D002116:Calcitonin; D002118:Calcium