PreladenantisapotentcompetitiveantagonistofthehumanA_2Areceptor(K_i=1.1nM)andhas>1000-foldselectivityoverallotheradenosinereceptors.

Ki:1.1nM(AdenosineA_2Areceptor)^[1]

PreladenantalsocompletelyantagonizescAMPincellsexpressingtherecombinanthumanA_2Areceptor.PreladenantisdeterminedtohasK_Bvaluesof1.3nMattheA_2Areceptor;thevalueisingoodagreementwiththeK_ivaluedeterminedintherADIoligandbindingassay.AsimilarfunctionalassaywithA_2Breceptor-expressingcellsisusedtodemonstrateselectivityoverA_2Breceptors.Inthisassay,theK_BvalueforPreladenantis1.2μM,indicatingthatPreladenantis923-foldselectivefortheA_2AreceptorovertheA_2Breceptor^[1].

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].

• [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.

Receptorbindingisperformedusingmembranespreparedfromcellswithrecombinantexpressionofadenosinereceptorsasfollows:humanA_2AandHEK293,ratA_2AandChinesehamsterovary,humanandratA1andChinesehamsterovary,andhumanA₃andHEK293.Radioligandcompetitionbindingassaysareperformedin96-wellplatesinatotalassayvolumeof200μLusingafinaltestdrugconcentrationrangeofbetween0.1and3μM.Membranesaredilutedinassaybuffer,pH7.4(A₁andA_2A,Dulbecco"sphosphate-bufferedsalinewith10mMMgCl₂;A₃,50mMTris-HCl,120mMNaCl,10mMMgCl₂).Toremoveendogenousadenosinefromthemembranepreparations,4U/mLadenosinedeaminaseisaddedtothemembranes,whicharethenincubatedatroomtemperaturefor15min.Radioligandisaddedtoafinalconcentrationof0.5([³H]SCH58261,A_2A),1([³H]DPCPX,A₁),or0.25([¹²⁵I]AB-MECA,A₃)nM.Nonspecificbindingisdefinedbyadding100nMCGS15923(A_2A),100nMNECA(A₁),or100nMDPCPX(A₃).Platesareincubatedatroomtemperaturewithagitationfor1.5h(A_2AandA₁)or2h(A₃).MembranesarefilteredontoPackardGF-Bfilterplatesandwashedinice-coldassaybufferusingaBrandelcellharvestertoseparateboundandfreeradioligand.Theplatesaredriedbeforeadditionof45μLofMicroscint20toeachwell.IC₅₀valuesaredeterminingbyfittingthedisplacementcurvesusinganiterativecurve-fittingprogram.K_ivaluesarecalculatedusingtheCheng-Prusoffequation^[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

PreladenantisdissolvedinDMSOandstored,andthendilutedwithappropriatemediabeforeuse^[1].

HEK293cellsstablyexpressingeitherhumanA_2AorA_2Breceptorsaregrowntoconfluence,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(A_2A)or5-N-cyclopropylcarboxamidoadenosine(A_2B)at10-foldthedesiredconcentrationisthenadded,andthereactionsareincubatedfor15minat37°C.Thereactionsareterminatedbytheadditionof50μLofassay/lysisbuffer.TheconcentrationresponsecurvesforCGS-21680inthepresenceandabsenceofPreladenantareplotted,andtheEC₅₀valuesaredeterminedbyfittingthecurvesusingGraphPadPrismsoftware^[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

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.

• [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.

503.56

C₂₅H₂₉N₉O₃

377727-87-2

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO

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

Purity:99.08%

SelectBatch:HY-10889-07975HY-10889-07680

DataSheet(120KB)SDS(120KB)

COA(93KB)HNMR(164KB)LCMS(186KB)

HandlingInstructions(1252KB)

• [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.

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托烷司琼临床评价药物相关作用适应症托烷司琼CAS号:89565-68-4英文名称:Tropisetron英文同义词:icf205-930;TROPICACID;TROPISETRON;SS-TROPISETRON;BETA-TROPISETRON;Tropisetron(ICS205930);TROPISHTRONHYDROCHLORIDE;Indole-3-carbonylchloride;3-Tropanylindole-3-carboxylate;lαH，5Αh-Tropan-3α-ylindole-3-carboxylate中文名称:托烷司琼中文同义词:托普西隆;托普西龙;曲匹西龙;托烷司琼;Β-托烷司琼;CS-348;Β-内托烷司琼;吲哚-3-甲酰氯;Β-托烷司琼(光学异构体);Β-托烷司琼,托烷司琼异构体CBNumber:CB3236404分子式:C17H20N2O2分子量:284.35MOLFile:89565-68-4.mol化学性质安全信息用途供应商112化学性质安全信息用途供应商112托烷司琼化学性质熔点:201-202°C沸点:448.5±35.0°C(Predicted)密度:1.26储存条件:2-8°C溶解度:H2O:soluble形态:solid酸度系数(pKa):15.38±0.30(Predicted)颜色:whiteCAS数据库:Chemicalbook89565-68-4(CASDataBaseReference)安全信息WGKGermany:3托烷司琼化学药品说明书托烷司琼|药物应用信息托烷司琼性质、用途与生产工艺临床评价Sorbe等报道本品对含顺铂(剂量50～89mg/m2)化疗方案引起的急性呕吐完全控制率为63%。58例恶性肿瘤化疗所致恶心、呕吐者，应用托烷司琼或昂丹司琼8mg分别在同一病人前后2个化疗周期的第1d给药前30min静脉注射，并用地塞米松10mg静脉滴注。结果两药控制急性及迟发性恶心、呕吐的疗效基本相似，均可达81%～100%。本品对强致吐化疗药物顺铂的止吐疗效突出。药物相关作用饮食可略为延长本品的吸收。本品与利福平、苯巴比妥等肝酶诱导药同时使用，可加快代谢，故快代谢型者需增加剂量，慢者则不必。西咪替丁等肝酶抑制药对本品血药浓度无明显影响。适应症托烷司琼临床用于预防和治疗癌症化疗引起的恶心和呕吐。化学性质结晶，熔点201-202℃(二氯甲烷-乙酸乙酯)。单盐酸托烷司琼(TropisetronMonohydroehloride)：C17H20N2O2?HCI。[105826-92-4]。熔点283-285℃(分解)。用途有高效性和选择性的5-HT3受体拮抗剂。用于化疗所致的呕吐。用途为5-羟色胺拮抗药生产方法托品醇(I)和酰氯(Ⅱ)反应，可得托烷司琼。托烷司琼上下游产品信息上游原料托品醇下游产品

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托烷司琼临床评价药物相关作用适应症托烷司琼CAS号:89565-68-4英文名称:Tropisetron英文同义词:icf205-930;TROPICACID;TROPISETRON;SS-TROPISETRON;BETA-TROPISETRON;Tropisetron(ICS205930);TROPISHTRONHYDROCHLORIDE;Indole-3-carbonylchloride;3-

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