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Medchemexpress/NPS-2143(Synonyms: SB 262470A)/HY-10007/10mM*1mL in DMSO
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- •AmJPhysiolHeartCircPhysiol.2010Nov;299(5):H1309-17.
Description | NPS-2143isanovelpotentandselectiveantagonistof Ca2+receptor with IC50 of43nM. |
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IC50&Target | IC50:43nM(Ca2+receptor) |
InVitro | NPS-2143blocksincreasesincytoplasmicCa2+ concentrationswithIC50of43nMelicitedbyactivatingtheCa2+receptorinHEK293cellsexpressingthehumanCa2+ receptor. NPS-2143stimulatesparathyroidhormone(PTH)secretionfrombovineparathyroidcellswithEC50of41nM.Moreover,NPS214alsoblockstheinhibitoryeffectsofcalcimimeticNPSR-467onPTHsecretionfrombovineparathyroidcellsandtheinhibitoryeffectsofextracellularCa2+onisoproterenol-stimulatedincreasesincyclicAMPformation[1]. InHEK-293cellstransientlyexpressinghCaSRs,NPS-2143significantlysuppressesthekokumitastebyeffectivelyinhibitingtheactivityofbothGSHandγ-Glu-Val-Gly[3]. ArecentstudyshowsthatNPS-2143treatmentsuppresseslowmolecularweightfractionsofazukihydrolysate-inducedcholecystokinin(CCK)secretioninCaSR-transfectedHEK293cells[4]. |
InVivo | NPS-2143resultsinarapid4-to5-foldincreaseinplasmaPTHlevelsandalsoatransientincreaseinplasmaCa2+ levels[1]inrats. Innormotensiverats,NPS-2143administration(1mg/kg,i.v.)markedlyincreasesmeanarterialbloodpressure(MAP)inthepresenceofparathyroidglands[2]. |
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Pleaserefertothesolubilityinformationtoselecttheappropriatesolvent. | ||||||||||||||||
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KinaseAssay [1] | Thisclonalcellline,referredtoasHEK2934.0-7cells,areusedinahigh-throughputscreeningformattodetectagonistsandallostericactivatorsoftheCa2+ receptor.Changesintheconcentrationofcytoplasmic[Ca2+]iprovideaquantitativeandfunctionalassessmentofCa2+receptoractivityinthesecellsandtheresultsusingthisassayparallelthoseobtainedusingahomologousexpressionsystemofbovineparathyroidcells.On-linecontinuousmeasurementsoffluorescenceinfluo-3-orfura-2-loadedHEK2934.0-7cellsareobtainedusingacustom-builtspectrofluorimeterorafluorescenceimagingplatereaderinstrument.NPS-2143isincubatedwithcellsfor1minutebeforeincreasingtheconcentrationofextracellularCa2+ from1.0mMto1.75mM.NPS-2143istestedindividuallyataconcentrationof100μg/mL(20μM-80μM)andthosecausingmorethana40%inhibitionofthecontrolresponseareconsideredtobeBIOLOGicallyactive.Todeterminethepotencies(IC50)ofNPS-2143withbiologicalactivity,concentration-responsecurvesareobtainedandthen,asaninitialassessmentofselectivity,theeffectsofNPS-2143on[Ca2+]ievokedbyotherGprotein-coupledreceptorsareexaminedataconcentrationseveraltimestheirIC50.Wild-typeHEK293cells(andHEK2934.0-7cells)expressreceptorsforthrombin,bradykinin,andATP,whichcoupletothemobilizationofintracellularCa2+.TheseresponsescanbestudiedtoquicklyassessanynonselectiveactionofcompoundsonGprotein-coupledreceptors.AdditionalassaysforselectivityincludeHEK293cellsengineeredtoexpressreceptorsmosthomologousinsequenceandtopologytotheCa2+receptor.Theseincludenativeorchimericreceptorsforvariousmetabotropicglutamateandγ-aminobutyricacidtypeBreceptors(GABABRs).ChimericreceptorsarecreatedusingpartialsequencesofmetabotropicglutamatereceptorsandCa2+ receptors,engineeredtocoupletoactivationofphospholipaseCandreleaseofintracellularCa2+ inHEK293cells.NPS-2143lackingpan-activityarethensubjectedtostructuralmodificationsandtheirpotenciesandselectivitiesmonitoredusingtheseHEK2934.0-7cellassaysinaniterativeprocess.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly. | ||||||||||||||||
AnimalAdministration [1] | NPS-2143isformulatedin20%aqueoussolutionof2-hydroxypropyl-β-cyclodextrin. Onthedayofstudy,theratsareinfusedintravenously(0.1mL/kg·min)for120minwithNPS-2143(0.1μmol/kg·min)orvehicle,a20%aqueoussolutionof2-hydroxypropyl-β-cyclodextrin.Bloodsamples(0.5mL)arecollectedbeforeandatvarioustimesafterthestartoftheinfusionformeasurementsofplasmalevelsofPTHandCa2+.Topreventexcessivebloodvolumelossduringthecourseoftheexperiment,foreachbloodsampletheerythrocytepelletisresUSPendedinanequalvolumeofnormalratplasmaandreinjected.PlasmalevelsofCa2+ aremeasuredimmediatelyaftercollectionusingamodel634ionizedcalciumanalyzer.PTHlevelsaremeasuredusingtheImmutopicsratPTH(1-34)immunorADIometricassaykit.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly. | ||||||||||||||||
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MolecularWeight | 408.92 | ||||||||||||
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Formula | C₂₄H₂₅ClN₂O₂ | ||||||||||||
CASNo. | 284035-33-2 | ||||||||||||
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Shipping | RoomtemperatureincontinentalUS;mayvaryelsewhere | ||||||||||||
Solvent&Solubility | 10mMinDMSO NPS-2143isdissolvedintoDMSOas10mMofstocksolution,andaliquotsaredilutedinto100mLperfusionbufferjustbeforeuse[5]. *"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">1> | ||||||||||||
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Purity:99.42%