NPS-2143 hydrochloride

NPS-2143(SB 262470A ) is a selective potent calcium ion-sensing receptor antagonist with IC50 of 43 and 41 nM for cytoplasmic Ca2+ concentrations and parathyroid hormone secretion, respectively.IC50 value: 43 nM(for Ca2+ receptor) [1]Target: CaSRin vitro: NPS 2143, even when tested at much higher concentrations (3 microM), did not affect the activity of a number of other G protein-coupled receptors, including those most structurally homologous to the Ca2+ receptor. NPS 2143 stimulated parathyroid hormone (PTH) secretion from bovine parathyroid cells (EC50 of 41 nM) over a range of extracellular Ca2+ concentrations and reversed the effects of the calcimimetic compound NPS R-467 on [Ca2+]i and on secretion of PTH [1]. The first reported calcilytic compound was NPS 2143, an orally active molecule which elicits rapid, 3- to 4-fold increases in circulating levels of PTH [2].in vivo: When infused intravenously in normal rats, NPS 2143 caused a rapid and large increase in plasma levels of PTH. Ca2+ receptor antagonists are termed calcilytics and NPS 2143 is the first substance (either atomic or molecular) shown to possess such activity [1]. When administered together with an antiresorptive agent (estradiol), NPS 2143 causes an increase in trabecular bone volume and bone mineral density in osteopenic rats [2].

Signaling Pathways >> GPCR/G Protein >> CaSR

Research Areas >> Metabolic Disease

[1]. Huang Y, Breitwieser GE. Rescue of calcium-sensing receptor mutants by allosteric modulators reveals a conformational checkpoint in receptor biogenesis. J Biol Chem. 2007 Mar 30;282(13):9517-25

[2]. Marquis, Robert W.; Lago, Amparo M.; Callahan, James F.;Antagonists of the Calcium Receptor. 2. Amino Alcohol-Based Parathyroid Hormone Secretagogues. Journal of Medicinal Chemistry (2009), 52(21), 6599-6605.

[3]. Yamamura A, Guo Q, Yamamura H, Zimnicka AM, Pohl NM, Smith KA, Fernandez RA, Zeifman A, Makino A, Dong H, Yuan JX.Enhanced Ca2+-sensing receptor function in idiopathic pulmonary arterial hypertension.Circ Res. 2012 Aug 3;111(4):469-81. Epub 2012 Jun 22.

[4]. Nakajima S, Hira T, Hara H.Calcium-sensing receptor mediates dietary peptide-induced CCK secretion in enteroendocrine STC-1 cells.Mol Nutr Food Res. 2012 May;56(5):753-60.

[5]. Davey AE, Leach K, Valant C, Conigrave AD, Sexton PM, Christopoulos A.Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor.Endocrinology. 2012 Mar;153(3):1232-41. Epub 2011 Dec 30.

[6]. Nemeth EF, et al. Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther. 2001 Oct;299(1):323-31.

NPS-2143 | Evocalcet | Strontium Ranelate | Calcium-Sensing Receptor Antagonists I | SB-423562