Pridopidine-hydrochloride-ACR16-hydrochloride-生命科學(xué)試劑-MCE

Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemEPridopidinehydrochlorideCat.No.:HY-111210CASNo.:882737-42-0Synonyms:ACR16hydrochloride;ASP2314hydrochloride;FR310826hydrochloride分子式:C??H??ClNO?S分子量:317.87作用靶點(diǎn):DopamineReceptor作用通路:GPCR/GProtein;NeuronalSignaling儲(chǔ)存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性Pridopidine(ACR16)hydrochloride是一種多巴胺(DA)穩(wěn)定劑，可用作一種低親和力的多巴胺D2受體(D2R)拮抗劑。Pridopidine高親和力作用于sigma1受體(S1R)，Ki值為70到80nM，比其對(duì)D2R的親和力高約100倍。IC50&TargetKi:70-80nM(sigma1receptor)[1]Dopamine[1]DopamineD2receptor[1]體外研究Pridopidine,adopamine(DA)stabilizer,PridopidinemaybeaneuromodulatoryagentwithneuroprotectivepropertiesinHuntingtondisease(HD).ToclarifytheneuroprotectiveefficacyofPridopidineandtoexplorethepotentialunderlingmolecularmechanism,theabilityofPridopidineisevaluatedtoprotectcellsfromapoptosisandtoeventuallyactivatepro-survivaltargets.AdministrationofPridopidine(150μM),themosteffectivedose,significantlyreducesapoptosisinimmortalizedstriatalknock-incellsexpressingendogenouslevelsofmutantHtt(STHdh111/111)andmarkedlyenhancesphosphorylationstateofprosurvivalkinaseERK[2].體內(nèi)研究PridopidineisknowntoactasalowaffinityD2Rantagonist.Pridopidine’sactivitymaybeattributedtobindingthesigma1receptor(S1R),anendoplasmicreticulum(ER).TostrengthenthehypothesisthattheBDNFpathwayisupregulatedduetoactivationoftheS1R,SDratsaretreatedwithlowerdosesofPridopidine(range0.3-60?mg/kg),andanalysedtheexpressionofsevenselectedgenesintheBDNFpathwaybyqPCR.Pridopidinedosesof3and15?mg/kginratsoccupy57±2%and85±2%ofS1R,1/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemErespectively,andbothdonotshowoccupancyoftheD2R,asdeterminedbyinvivoPETimaging.ThesignificantoccupancyproportionoftheD2R(44-66%)isobservedonlyatadoseof60?mg/kg.ThisPETstudysupportstheconclusionthattheupregulationofgenesinratstreatedwith15?mg/kgPridopidinearearesultofspecificactivationoftheS1R.At30?mg/kg,partial/lowoccupancyoftheD2Risatlevelsof22-33%(assuminglinearity),andS1Rissaturated.Indeed,qPCRanalysisrevealsthattheupregulationofEGR1(alreadyupat3?mg/kg),EGR2,HOMER1A,KLF5,andARCexpressionareupregulatedatthelow15?mg/kgdoseandexpressionofCDNK1AandCEBPBaresignificantlyupregulatedfromalowdoseof30?mg/kg(CEBPBissignificantlyincreasedat3?mg/kgbutnotat15?mg/kg)[1].TofurtherconfirmthebeneficialeffectofPridopidineonHDmotorphenotypeandtoelucidatewhetherPridopidinemayactalsoasneuroprotectiveagent,preclinicalstudiesinR6/2micehavebeenundertaken.DailyadministrationofPridopidineatadoseof5mg/kg,themosteffectivedosewithnoadverseeffects,startingatthepre-symptomaticstageat5weeksfor6weeks,significantlypreservesmotorfunctionandpreventstheprogressiveanddramaticmotorworseningcommonlyobservedinR6/2mice.ThebeneficialeffectsofPridopidinearemaintainedforabout4weeks,afterwhichmiceshowaslightworseninginperformingboththehorizontalladdertaskandtheopenfield.Inaddition,accordingtoaKaplan-Meiersurvivalcurveanalysis,Pridopidineefficientlyextendslifespaninthesamemice[2].PROTOCOLCellAssay[2]Conditionallyimmortalizedmousestriatalknock-incellsexpressingendogenouslevelsofwild-type(STHdh7/7)ormHtt(STHdh111/111)areused.DifferentconcentrationsofPridopidine(100,150,200and300μM)aretestedtoinvestigatetheanti-apoptoticeffectofthemoleculeonimmortalizedcellsculturedinserum-freemediumat39°Cforsixhours.InNE100experiments,cellsarepre-incubatedwiththecompound(10μM)for2hrsbeforeculturingtheminapoptoticconditions.Attheendofeachtreatment,cellsarecollectedandincubatedwithFITC-conjugatedAnnexinV.FluorescenceActivatedCellSorting(FACS)analysisisperformed[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalRats[1]Administration[1][2]SpragueDawley(SD)malerats(n=6pergroup)aretreateddailybyoralgavagewithPridopidineatadoseof60?mg/kgorvehicle(water)overthecourseof10days.Onday10,90?minfollowinglastdrug/wateradministration,brainsareremoved,andquicklyrinsedwithcoldphysiologicalsaline.Thestriatumofthelefthemisphereisgentlyextractedandimmediatelyimmergedin1000μLofRNAlaterSolutioninpre-labelledpolypropylenevialsandstoredat4°Covernight(toallowthesolutiontothoroughlypenetratethetissue),thenmovedto-20°Cuntilanalysis.RNAisisolatedfromthestriatumofeachratandanalysed[1].Mice[2]AllinvivoexperimentsareconductedinR6/2transgenicmiceexpressingexon1ofhumanHttwithapproximately160±10(CAG)repeatsandmanifestingfirstsymptomsaroundweek7,andinwild-type(WT)littermatesmaintainedontheB6CBAstrain.Animalsarehousedsinglyandmaintainedundera12-hrlight/darkcycleenvironmentinacleanfacilityandgivenfreeaccesstofoodpelletsandwater.Pridopidineisdissolvedinsaline(vehicle),andadministereddailybyintraperitoneal(i.p.)injectionatadoseof5or6mg/kgperbodyweightduringthelightphaseofthecircadianrhythm.Controlmice(WTandR6/2)areinjecteddailywiththesamevolumeofvehicle.Allthemicearesinglyhousedinhomecage.Pridopidine(5mg/kg)is2/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEadministeredtopre-symptomaticmicestartingatweek5toweek11(6weekduration)andforsymptomaticanimalsstartingfromweek7toweek9(3weeksduration)and1weekofdailyadministration(6mg/kg)atweek10[2].MCE