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Medchemexpress/Preladenant(Synonyms: SCH-420814)/HY-10889/100mg
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Medchemexpress/Preladenant(Synonyms: SCH-420814)/HY-10889/100mg
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HY-10889-5mg
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PreladenantisapotentcompetitiveantagoNISTofthehumanA2Areceptor(Ki=1.1nM)andhas>1000-foldselectivityoverallotheradenosinereceptors.

CustomerValidation

  • •JNuclMed.2017May;58(5):762-767.
  • •JMedChem.2014Nov13;57(21):9204-10.
  • •PLoSOne.2016Nov11;11(11):e0166415.
  • •Shivashankar.2014.9.15.
Description

PreladenantisapotentcompetitiveantagonistofthehumanA2Areceptor(Ki=1.1nM)andhas>1000-foldselectivityoverallotheradenosinereceptors.

IC50&Target

Ki:1.1nM(AdenosineA2Areceptor)[1]

InVitro

PreladenantalsocompletelyantagonizescAMPincellsexpressingtherecombinanthumanA2Areceptor.PreladenantisdeterminedtohasKBvaluesof1.3nMattheA2Areceptor;thevalueisingoodagreementwiththeKivaluedeterminedintherADIoligandbindingassay.AsimilarfunctionalassaywithA2Breceptor-expressingcellsisusedtodemonstrateselectivityoverA2Breceptors.Inthisassay,theKBvalueforPreladenantis1.2μM,indicatingthatPreladenantis923-foldselectivefortheA2AreceptorovertheA2Breceptor[1].

InVivo

Preladenant(1mg/kg)inhibitsL-Dopa-inducedbehavioralsensitizationafterrepeateddailyadministration,whichsuggestsareducedriskofthedevelopmentofdyskinesias.Preladenantexhibitsantidepressant-likeprofilesinmodelsofbehavioraldespair,namelythemousetailsUSPensiontestandthemouseandratforcedswimtest[1].Preladenantproducesadose-dependentreductioninparkinsonianscoresatdosesof1mg/kg(minscore:9.0)and3mg/kg(minscore:6.5).AsubthresholddoseofPreladenantreducesminimumandmeanparkinsonianscoresinanimalstreatedwith3mgkgofL-Dopato5.25and6.88respectively.AWilcoxintestisusedtocompareindividualtreatmentsagainstvehicle.Preladenant(3mg/kg),L-Dopa(3,6,and12mg/kg),andthecombinationofPreladenantandL-Dopa(1or3mg/kg+3mg/kg)areallsignificantlyimprovedontheminimumparkinsonianscore.Inaddition,boththe12mg/kgL-DopaandL-Dopa+Preladenantgroupsaresignificantlyimprovedonbothminimumandmeanparkinsonianscoresrelativetothe3mg/kgL-Dopagroup[2].

ClinicalTrial
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References

  • [1].HodgsonRA,etal.CharacterizationofthepotentandhighlyselectiveA2AreceptorantagonistspreladenantandSCH412348[7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine]inrodent

    [2].HodgsonRA,etal.Preladenant,aselectiveA(2A)receptorantagonist,isactiveinprimatemodelsofmovementdisorders.ExpNeurol.2010Oct;225(2):384-90.

PreparingStockSolutions
ConcentrationVolumeMass1mg5mg10mg
1mM1.9859mL9.9293mL19.8586mL
5mM0.3972mL1.9859mL3.9717mL
10mM0.1986mL0.9929mL1.9859mL
Pleaserefertothesolubilityinformationtoselecttheappropriatesolvent.
KinaseAssay
[1]

Receptorbindingisperformedusingmembranespreparedfromcellswithrecombinantexpressionofadenosinereceptorsasfollows:humanA2AandHEK293,ratA2AandChinesehamsterovary,humanandratA1andChinesehamsterovary,andhumanA3andHEK293.Radioligandcompetitionbindingassaysareperformedin96-wellplatesinatotalassayvolumeof200μLusingafinaltestdrugconcentrationrangeofbetween0.1and3μM.Membranesaredilutedinassaybuffer,pH7.4(A1andA2A,Dulbecco"sphosphate-bufferedsalinewith10mMMgCl2;A3,50mMTris-HCl,120mMNaCl,10mMMgCl2).Toremoveendogenousadenosinefromthemembranepreparations,4U/mLadenosinedeaminaseisaddedtothemembranes,whicharethenincubatedatroomtemperaturefor15min.Radioligandisaddedtoafinalconcentrationof0.5([3H]SCH58261,A2A),1([3H]DPCPX,A1),or0.25([125I]AB-MECA,A3)nM.Nonspecificbindingisdefinedbyadding100nMCGS15923(A2A),100nMNECA(A1),or100nMDPCPX(A3).Platesareincubatedatroomtemperaturewithagitationfor1.5h(A2AandA1)or2h(A3).MembranesarefilteredontoPackardGF-Bfilterplatesandwashedinice-coldassaybufferusingaBrandelcellharvestertoseparateboundandfreeradioligand.Theplatesaredriedbeforeadditionof45μLofMicroscint20toeachwell.IC50valuesaredeterminingbyfittingthedisplacementcurvesusinganiterativecurve-fittingprogram.KivaluesarecalculatedusingtheCheng-Prusoffequation[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

CellAssay
[1]

PreladenantisdissolvedinDMSOandstored,andthendilutedwithappropriatemediabeforeuse[1].

HEK293cellsstablyexpressingeitherhumanA2AorA2Breceptorsaregrowntoconfluence,harvestedusingenzyme-freecelldissociationbufferandpelletedbycentrifugation(1000g;5min).Thecellsarewashedanddilutedtoafinaldensityof4×106cells/mLinHanks"balancedsaltsolutionsupplementedwith10nMHPS,pH7.4,,5mMMgCl2,and0.2%bovineserumalbumin.Preladenantisdilutedintheabovebufferwithinclusionofthefollowingcomponentstoachievetherespectivefinalassayconcentrations:0.25%DMSO,2U/mLadenosinedeaminase,and100μMRo201724.Cellsuspensions(20μL)arepreincubatedfor15minatroomtemperaturein96-wellplatescontaining25μLofvehicleorPreladenant.CGS-21680(A2A)or5-N-cyclopropylcarboxamidoadenosine(A2B)at10-foldthedesiredconcentrationisthenadded,andthereactionsareincubatedfor15minat37°C.Thereactionsareterminatedbytheadditionof50μLofassay/lysisbuffer.TheconcentrationresponsecurvesforCGS-21680inthepresenceandabsenceofPreladenantareplotted,andtheEC50valuesaredeterminedbyfittingthecurvesusingGraphPadPrismsoftware[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

AnimalAdministration
[1][2]

Preladenantispreparedin50%polyethyleneglycol400(RatandMice)[1].
Preladenantisdissolvedincyclodextrin,sonicatedandadministeredp.o.forthestudy(Monkey)[2].

MiceandRat[1]
MaleCDratsandmaleCD1miceareused.Preladenantisadministeredorallyin50%polyethyleneglycol400atadosevolumeof3to5mL/kg.Intheforcedswimtest(FST),miceareplacedindividuallyintoglasscylindersfilledtoadepthof10cmwithwater(25°C)andleftfor6min.Amouseisjudgedtobeimmobilewhenitfloatsinanuprightpositionandmadeonlysmallmovementstokeepitsheadabovewater.Thedurationofimmobilityisrecordedduringthelast4minofthe6-mintestingperiodbyanobserverblindtothetreatmentoftheanimals.Animalsaredosedwithvehicle,Preladenant,orSCH4123481hbeforebehavioraltesting.Eachratisplacedindividuallyinacylinderofwater(25°C)andlefttoswimfor15minbeforebeingremovedanddriedinaheatedenclosureandreturneditshomecage.Twenty-fourhourslater(testday),theanimalisre-exposedtotheconditions,andthetotalimmobilitytimeduringa5-minperiodisrecorded.Inaddition,thedurationoftimethattheratsspentclimbingthesidesofthecylinderisrecorded.Ontestday,eachanimalisdosedwithPreladenant,SCH412348,orvehicle1hbeforebehavioraltesting.
Monkey[2]
Sixfemalecynomolgus(Macacafascicularis)monkeys(weighing3.5-4.2kg)areused.Theanimalsarerenderedparkinsonianbysubcutaneous(sc)administrationsofMPTP(2-3mg/kg)onceperweekuntilastableparkinsoniansyndrome(unchangeddisABIlityscoreof8orgreaterforatleastamonth)developedasmeasuredbyaparkinsoniandisabilityscale.Atleast2monthsafterthefinaladministrationofMPTP,themonkeysaretreatedchronicallywithProlopa(L-Dopa/benserazide,100/25mg)untilclearandreproducIBLedyskinesiasdeveloped.ThepresentexperimentwithL-DopaandPreladenant(1mg/kgand3mg/kg,p.o.)isperformedinthesemonkeys.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

References

  • [1].HodgsonRA,etal.CharacterizationofthepotentandhighlyselectiveA2AreceptorantagonistspreladenantandSCH412348[7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine]inrodent

    [2].HodgsonRA,etal.Preladenant,aselectiveA(2A)receptorantagonist,isactiveinprimatemodelsofmovementdisorders.ExpNeurol.2010Oct;225(2):384-90.

MolecularWeight

503.56

Formula

C₂₅H₂₉N₉O₃

CASNo.

377727-87-2

Storage
Powder-20°C3years
 4°C2years
Insolvent-80°C6months
 -20°C1month
Shipping

RoomtemperatureincontinentalUS;mayvaryelsewhere

Solvent&Solubility

DMSO

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

Purity:99.08%

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