Calcimimetic compound NPS R-568 stimulates calcitonin secretion but selectively targets parathyroid gland Ca(2+) receptor in rats.
N-(3-[2-Chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine (NPS R-568) is an orally active compound that activates Ca(2+) receptors on parathyroid cells and rapidly suppresses plasma levels of parathyroid hormone (PTH) and Ca(2+) (ED(50), 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 Ca(2+) levels, indicating that decreased PTH secretion was not solely responsible for the hypocalcemia seen in normal animals. NPS R-568 decreased plasma Ca(2+) 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 Ca(2+) 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 (ED(50) 40 mg/kg). NPS R-568 did not affect the rate of disappearance of (45)Ca from blood, indicating that hypocalcemia resulted from decreased influx of Ca(2+) into the circulation and not from increased efflux. This suggests that NPS R-568-induced hypocalcemia resulted solely from reduced efflux of Ca(2+) from bone after increased calcitonin and reduced PTH secretion. Thus, NPS R-568 causes hypocalcemia by activating Ca(2+) 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.
Fox
J
J
NPS Pharmaceuticals, Inc., Salt Lake City, Utah, USA. jfox@npsp.com
Lowe
S H
SH
Conklin
R L
RL
Petty
B A
BA
Nemeth
E F
EF
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002116:Calcitonin / Q000097:blood*; D002118:Calcium / Q000097:blood*; D002125:Calcium Gluconate / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006996:Hypocalcemia / Q000097:blood / Q000517:prevention & control; D007700:Kinetics; D008297:Male; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism*; D016105:Parathyroidectomy; D010627:Phenethylamines; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D013965:Thyroidectomy
D000814:Aniline Compounds; D002135:Calcium-Binding Proteins; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D002116:Calcitonin; D002125:Calcium Gluconate; D002118:Calcium