R 568 hydrochloride

Effect of the calcimimetic R-568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on correcting inactivating mutations in the human calcium-sensing receptor.[Pubmed:19759318]

J Pharmacol Exp Ther. 2009 Dec;331(3):775-86.

Over 257 mutations in the human calcium-sensing receptor (hCaSR) gene have been reported. Heterozygous inactivating mutations can result in familial hypocalciuric hypercalcemia (FHH), whereas homozygous inactivating mutations can cause life-threatening neonatal severe hyperparathyroidism (NSHPT). Activating mutations in the hCaSR can result in hypercalciuria and hypocalcemia. A recent publication on the successful treatment of a patient suffering from FHH with the hCaSR positive allosteric modulator cinacalcet prompted our interest in exploring the molecular pharmacology of calcimimetics to correct signaling defects associated with inactivating hCaSR mutations. We prepared 11 mutant hCaSRs, previously identified in patients suffering from NSHPT or FHH, and tested their ability to couple to inositol phosphate accumulation and intracellular calcium mobilization in transiently transfected human embryonic kidney 293 and Chines hamster ovary cells using the calcimimetic R-568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine]. We found that extracellular Ca(2+) was significantly less potent on the mutated receptors compared with wild-type hCaSR. However, R-568 was able to enhance the potency of extracellular Ca(2+) toward the mutant hCaSRs. Furthermore, R-568 increased the maximal agonist response on several of the mutant CaSRs. We applied a novel operational model of allosteric modulation/agonism that provided a common mechanism to account for the behavior of the wild-type and mutant hCaSRs. The data provide evidence for the potential use of calcimimetics to treat diseases such as FHH and NSHPT where severe hypercalcemia can be life-threatening.

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.[Pubmed:10411552]

J Pharmacol Exp Ther. 1999 Aug;290(2):473-9.

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.

The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor.[Pubmed:9399943]

J Clin Invest. 1997 Dec 15;100(12):2977-83.

Parathyroid (PT) cell hyperplasia is a common consequence of chronic renal insufficiency (CRI). NPS R-568 is a phenylalkylamine compound that acts as an agonist (calcimimetic) at the cell surface calcium receptor (CaR). To test the hypothesis that the CaR plays a role in PT hyperplasia in CRI, we tested the effect of NPS R-568 on PT cell proliferation in rats with renal insufficiency. Rats were subjected to 5/6 nephrectomy and then infused intraperitoneally with 5-bromodeoxyuridine (BrdU) to label S-phase cells. Two groups of nephrectomized rats received NPS R-568 by gavage twice daily for 4 d (1.5 and 15 mg/kg body wt). On day 5, the number of BrdU-positive PT cells of vehicle-treated nephrectomized rats was 2.6-fold greater than that of the sham-operated control. Low and high doses of NPS R-568 reduced the number of BrdU-positive PT cells by 20 and 50%, respectively. No changes in staining, however, were observed in ileal epithelial cells (CaR-negative) or in thyroidal C-cells (CaR-positive). Furthermore, the effect of NPS R-568 could not be explained by changes in serum 1,25(OH)2D3 or phosphorus. These results indicate that NPS R-568 suppresses PT cell proliferation in rats with renal insufficiency, and lend support to the linkage between the CaR and PT hyperplasia in CRI.

Tecalcet Hydrochloride (R 568 Hydrochloride), an orally active calcimimetic compound, allosterically and positively modulates the calcium-sensing receptor (CaSR). Tecalcet Hydrochloride (R 568 Hydrochloride) increases the sensitivity to activation by extracellular Ca2+.

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