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NPS-2143 Catalog No.GC16943

CaSR antagonist

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5mg
$44.00
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10mg
$57.00
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50mg
$215.00
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200mg
$655.00
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Sample solution is provided at 25 µL, 10mM.

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Protocol

Kinase experiment:

This clonal cell line, referred to as HEK 293 4.0-7 cells, are used in a high-throughput screening format to detect agonists and allosteric activators of the Ca2+ receptor. Changes in the concentration of cytoplasmic [Ca2+]i provide a quantitative and functional assessment of Ca2+ receptor activity in these cells and the results using this assay parallel those obtained using a homologous expression system of bovine parathyroid cells. On-line continuous measurements of fluorescence in fluo-3- or fura-2-loaded HEK 293 4.0-7 cells are obtained using a custom-built spectrofluorimeter or a fluorescence imaging plate reader instrument. NPS-2143 is incubated with cells for 1 minute before increasing the concentration of extracellular Ca2+ from 1.0 mM to 1.75 mM. NPS-2143 is tested individually at a concentration of 100 μg/mL (20 μM-80 μM) and those causing more than a 40% inhibition of the control response are considered to be biologically active. To determine the potencies (IC50) of NPS-2143 with biological activity, concentration-response curves are obtained and then, as an initial assessment of selectivity, the effects of NPS-2143 on [Ca2+]i evoked by other G protein-coupled receptors are examined at a concentration several times their IC50. Wild-type HEK 293 cells (and HEK 293 4.0-7 cells) express receptors for thrombin, bradykinin, and ATP, which couple to the mobilization of intracellular Ca2+. These responses can be studied to quickly assess any nonselective action of compounds on G protein-coupled receptors. Additional assays for selectivity include HEK 293 cells engineered to express receptors most homologous in sequence and topology to the Ca2+ receptor. These include native or chimeric receptors for various metabotropic glutamate and γ-aminobutyric acid type B receptors (GABABRs). Chimeric receptors are created using partial sequences of metabotropic glutamate receptors and Ca2+ receptors, engineered to couple to activation of phospholipase C and release of intracellular Ca2+ in HEK 293 cells. NPS-2143 lacking pan-activity are then subjected to structural modifications and their potencies and selectivities monitored using these HEK 293 4.0-7 cell assays in an iterative process.

Animal experiment:

Rats: On the day of study, the rats are infused intravenously (0.1 mL/kg·min) for 120 min with NPS-2143 (0.1 μmol/kg·min) or vehicle, a 20% aqueous solution of 2-hydroxypropyl-β-cyclodextrin. Blood samples (0.5 mL) are collected before and at various times after the start of the infusion for measurements of plasma levels of PTH and Ca2+. To prevent excessive blood volume loss during the course of the experiment, for each blood sample the erythrocyte pellet is resuspended in an equal volume of normal rat plasma and reinjected. Plasma levels of Ca2+ are measured immediately after collection using a model 634 ionized calcium analyzer. PTH levels are measured using the Immutopics rat PTH(1-34) immunoradiometric assay kit.

References:

[1]. 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.
[2]. Rybczynska A, et al. Hypertensive effect of calcilytic NPS 2143 administration in rats. J Endocrinol. 2006 Oct;191(1):189-95.
[3]. Ohsu T, et al. Involvement of the calcium-sensing receptor in human taste perception. J Biol Chem. 2010 Jan 8;285(2):1016-22
[4]. Nakajima S, et al. 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]. Sun J, et al. Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart. Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1309-17.

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Chemical Properties

Cas No. 284035-33-2 SDF
Chemical Name 2-chloro-6-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile
Canonical SMILES CC(C)(CC1=CC2=CC=CC=C2C=C1)NCC(COC3=C(C(=CC=C3)Cl)C#N)O
Formula C24H25ClN2O2 M.Wt 408.93
Solubility ≥40.9mg/mL in DMSO Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Background

NPS-2143 is a novel and selective antagonist of CaSR (Ca2+-sensing receptor) with the EC50 value of 4.27mM for [Ca2+]o [1].

Calcilytics NPS-2143 has been reported to diminish the sensitivity of the CaSR for [Ca2+]o, resulting in an attenuated signal transduction in vitro and increased secretion of PTH in vivo. In addition, The EC50 values of NPS-2143 are 4.27, 1.56, 1.61, 2.46, 2.07 and 3.15mM for the wild-type CaSR, mutant CaSR (T151R, P221L, E767Q, G830S, and A844T), respectively. Apart from these, in HEK 293T cells expressing CaSR, NPS-2143 has been revealed to inhibit the [Ca2+]o-induced cytosolic calcium signal in a concentration-dependent manner [1].

References:
[1] Letz S1, Rus R, Haag C, Dörr HG, Schnabel D, Möhlig M, Schulze E, Frank-Raue K, Raue F, Mayr B, Schöfl C. Novel activating mutations of the calcium-sensing receptor: the calcilytic NPS-2143 mitigates excessive signal transduction of mutant receptors. J Clin Endocrinol Metab. 2010 Oct;95(10):E229-33.

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