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    NPS-2143 (SB-262470)
    NPS-2143 (SB-262470)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V1492
    CAS #: 284035-33-2Purity ≥98%

    Description: NPS-2143 (also known as SB-262470 and SB-262470A)  is a novel, potent and selective antagonist of calcium-sensing receptor (CaSR) with IC50 of 43 nM. NPS-2143 stimulates release of parathyroid hormone. Calcilytic drugs have been researched as potential treatments for osteoporosis, and as the first such compound developed, NPS-2143 is still widely used in research into the CaSR receptor as well as design of newer calcilytic agents. 

    References: J Pharmacol Exp Ther. 2001 Oct;299(1):323-31; J Endocrinol. 2006 Oct;191(1):189-95.

    Related CAS#: 284035-33-2 (free base); 324523-20-8 (HCl).

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    Molecular Weight (MW)408.92
    FormulaC24H25ClN2O2
    CAS No.284035-33-2
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 82 mg/mL (200.5 mM)
    Water: <1 mg/mL
    Ethanol:<1 mg/mL
    Solubility (In vivo)2% DMSO+Corn oil: 10mg/mL
    SynonymsSB262470; NPS-2143; NPS 2143; NPS2143; SB-262470; SB 262470; SB262470; SB-262470A.




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    In Vitro

    In vitro activity: NPS 2143 blocks increases in cytoplasmic Ca2+ concentrations with IC50 of 43 nM elicited by activating the Ca2+ receptor in HEK 293 cells expressing the human Ca2+ receptor. NPS 2143 stimulates parathyroid hormone (PTH) secretion from bovine parathyroid cells with EC50 of 41 nM. Moreover, NPS 214 also blocks the inhibitory effects of calcimimetic NPS R-467 on PTH secretion from bovine parathyroid cells and the inhibitory effects of extracellular Ca2+ on isoproterenol-stimulated increases in cyclic AMP formation. In HEK-293 cells transiently expressing hCaSRs, NPS 2143 significantly suppresses the kokumi taste by effectively inhibiting the activity of both GSH (data not shown) and γ-Glu-Val-Gly. A recent study shows that NPS 2143 treatment suppresses low molecular weight fractions of azuki hydrolysate-induced cholecystokinin (CCK) secretion in CaSR-transfected HEK 293 cells.


    Kinase Assay: 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.


    Cell Assay: 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.

    In VivoIn rats, NPS 2143 results in a rapid 4- to 5-fold increase in plasma PTH levels and also a transient increase in plasma Ca2+ levels. In normotensive rats, NPS 2143 administration (1 mg/kg) by i.v. markedly increases mean arterial blood pressure (MAP) in the presence of parathyroid glands.
    Animal modelChronic indwelling catheters are implanted in the inferior vena cava and in the abdominal aorta of male Sprague-Dawley rats. 
    Formulation & DosageDissolved in 20% aqueous solution of 2-hydroxypropyl-β-cyclodextrin; ≤0.1 μmol/kg · min; i.v. administration
    ReferencesJ Pharmacol Exp Ther. 2001 Oct;299(1):323-31; J Endocrinol. 2006 Oct;191(1):189-95.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    NPS-2143

    Postischemic left ventricular rate pressure product (RPP) functional recovery and infarct size.  2010 Nov;299(5):H1309-17.

     

    NPS-2143

    Changes in cardioprotective signaling kinases.

    NPS-2143

    IPC and NPS2143 treatments did not change CaSR content.   2010 Nov;299(5):H1309-17.

     

    NPS-2143

    Distribution of caveolin-3 and CaSR among fractions prepared from perfusion, IPC, and NPS2143-treated IPC hearts.

    NPS-2143

    Distribution of cardioprotective signaling kinases among fractions prepared from perfusion, IPC, and NPS2143-treated IPC hearts.  2010 Nov;299(5):H1309-17.


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