Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemETC-2559freebaseCat.No.:HY-171807CASNo.:189274-78-0分?式:C??H??N?O分?量:206.28作?靶點:nAChR;STAT作?通路:MembraneTransporter/IonChannel;NeuronalSignaling;JAK/STATSignaling;StemCell/Wnt儲存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性TC-2559freebase?種α4β2煙堿型?酰膽堿受體(nAChR)激動劑，其EC50為0.18μM。TC-2559freebase對β4亞的nAChR因型(α2β4、α4β4和α3β4受體)的激動效?較弱，其EC50在10-30μM之間。TC-2559freebase能在體外增加??腹側(cè)被蓋區(qū)(VTA)中的多巴胺細(xì)胞放電，增強(qiáng)VTA多巴胺能神經(jīng)元的興奮性和爆發(fā)性?為。TC-2559freebase可抑制STAT3來發(fā)揮抗炎作?，緩解??的機(jī)械性異常疼痛，并改??認(rèn)知缺陷。TC-2559freebase可?于研究神經(jīng)疼痛[1][2][3][4][5]。體外研究TC-2559freebase(freebase)competeseffectivelywith[3H]-mocotinebinding(Ki=5nM)[1].TC-2559freebase(0-100nM)enhancesdopaminereleaseinratstriatalsynapticvesicles(EC50,E=97%)and86Rb+effluxinthalamicsynapticvesicles(EC50=367nM,E=107%),whileshowingnoactivityinTE671/RDorPC12cellsat1mM[1].TC-2559freebase(10μM,2h)cansignificantlyreduceneuronaldeathinthebraincellsoffetalmice[1].TC-2559freebase(200-500μM,3-6h)suppressestheupregulationofCC-chemokineligand3(CCL3)andinterleukin-1b(IL-1b)inmurinemacrophages[3].TC-2559freebase(500μM,1-6h)inhibitsthephosphorylationofsignaltransducerandactivatoroftranscription3(pSTAT3)inmurinemacrophages[3].TC-2559freebase(0.5mM,24h)suppressestheupregulationofinterleukin-1β(IL-1β)intheinjuredSCNafterPSLinmiceperitonealmacrophages[4].TC-2559freebaseshowsmuchweakerpotenciesonthegroupofβ4-containingnAChRsubtypes,α2β4,α4β4andα3β4receptors,withEC50sof14,12.5,>30,>100and>100μM,respectively[5].RT-PCR[3]1/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemECellLine:MousemacrophageJ774A.1cellsConcentration:20-500μMwithLPSIncubationTime:3and6hResult:SuppressedthemRNAexpressionsofCCL3andIL-1b.WesternBlotAnalysis[3]CellLine:MousemacrophageJ774A.1cellsConcentration:500μMwithLPSIncubationTime:1,3and6hResult:InhibitedtheupregulationofpSTAT3at6h.Hadnoeffectonpp65expressionat1and6h.體內(nèi)研究TC-2559freebase(freebase)(0.124-2.063mg/kg,s.c.,singledose)candose-dependentlyreversethememoryimpairmentcausedbycholinergicblockadeinratsattenuationofscopolamine-inducedamnesia[1].HC-2559(0.124-2.063mg/kgμmol/kg,s.c.,singledoseorfor5days)significantlyreduceserrorsinworkingmemory,andsustainablyimprovesworkingmemory[1].HC-2559(0.206-1.238mg/kg,s.c.,singledoseorfor14days)causesmotorinhibitionatasingleadministrationanddoesnotinducebehavioralsensitizationaftercontinuousadministration[1].TC-2559freebase(0.021-1.32mg/kg,i.v.,cumulativedosesorsingledose)activatesVTAdopamineneuronsthroughα4β2-likenAChRs[2].TC-2559freebase(0.47-4.70mg/kg,s.c.or20nmol,perineuralInjections,for3days)significantlyrelievesmechanicalallodyniainmicebehavioralmodel[4].TC-2559freebase(20nmol,perineuralInjections,for3days)suppressesmicroglialactivationintheSDHinducedbyperipheralnerveinjuryinmice[4].AnimalModel:Attenuationofscopolamine-inducedamnesiaestablishedinmaleSprague-Dawleyrats(200-350g)[1]Dosage:0.124,0.206,0.619,1.238and2.063mg/kg(0.6,1,3,6and10μmol/mg)Administration:SubcutaneousInjections(s.c.),singledoseResult:Attenuatedscopolamine-induceddecreaseofavoidancelatenciesof21.5satdosesof3and6μmol/kg.Exhibitedthemedianstep-throughlatenciesof88.7and105.7sfor3and6μmol/kg,respectively.AnimalModel:Radial-armmazeperformancemodelestablishedinmaleSprague-Dawleyrats(200-3502/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEg)[1]Dosage:0.124,0.206,0.619and1.238mg/kg(0.6,1,3and6μmol/mg)Administration:SubcutaneousInjections(s.c.),singledoseorfor5daysResult:Significantlyreducedthenumberofworkingmemoryerrorsat3and10μmol/kginDay1.Significantlyreducedworkingmemoryerrorsfollowing6daysofrepeatedadministrationat1,3,and6μmol/kg.AnimalModel:LocomotoractivitymodelestablishedinmaleSprague-Dawleyrats(200-350g)[1]Dosage:0.124,0.412and2.063mg/kgforacuteadministrationand0.721mg/kgforrepeatedadministrationAdministration:SubcutaneousInjections(s.c.),singledoseoroncedailyorfor14daysResult:Resultedinsignificantreductionsinhorizontalcountsatthe30-mintimepoint.Resultedinadose-dependentmonophasicchangeinlocomotorbehaviorwithasustainedhypolocomotionat60minforthe0.206mg/kgdose.Noapparentsensitizationdevelopedfollowingrepeatedadministration.AnimalModel:ElectrophysiologicalmodelestablishedinmaleSprague-Dawleyrats(260-350g)[2]Dosage:0.021-1.32mg/kgor0.66and1.32mg/kgAdministration:Intravenousinjection(i.v.),cumulativedosesorsingledoseResult:Increasethedischargefrequencyby185%-206%.Increasethepeakdischargefrequencyto141%at0.66mg/kg.inducedburstinginoneoftwononburstingVTADAneuronestested.Evokedasignificantincreaseinbothspontaneousandburstfiringforupto15minofthetestingperiodat1.32mg/kg.WereblockedbyDHbE,butnotbyMLA.AnimalModel:BehavioraltestinginmaleICRmiceaged4to5weeks[4]Dosage:0.470,1.41and4.70mg/kg(2.28,6.84and22.8μmol/kg)(s.c.)or20nmol(p.n.)Administration:SubcutaneousInjections(s.c.)orperineuralInjections(p.n.)for3daysResult:Significantlyincreasethemechanicalpainthresholdat22.8μmol/kgduringeithertheearly(days0–3)ormiddle/late(days7–10).ImprovedmechanicalallodyniawithSazetidineA(HY-14319A)withp.n.admisitraionduringtheearlyormiddlephase.3/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemERelievedmechanicalallodyniawithp.n.duringthelate(days21-24)phase.AnimalModel:MicroglialactivationassayinmaleICRmiceaged4to5weeks[4]Dosage:20nmolAdministration:PerineuralInjections(p.n.)for3daysResult:SuppressedmicroglialactivationintheSDHevaluatedbyIba1expression.Significantlydown-regulateinflammatorymarkerssuchasCD68,IRF5,andIL-1β.REFERENCES[1].BencherifM,etal.TC-2559:anovelorallyactiveligandselectiveatneuronalacetylcholinereceptors.EurJPharmacol.2000Dec1;409(1):45-55.[2].WangY,etal.TC-2559excitesdopaminergicneuronesintheventraltegmentalareabystimulatingalpha4beta2-likenicotinicacetylcholinereceptorsinanaesthetisedrats.BrJPharmacol.2006Feb;147(4):379-90.[3].KiguchiN,etal.TC-2559,anα4β2nicotinicacetylcholinereceptoragonist,suppressestheexpressionofCCL3andIL-1βthroughSTAT3inhibiti