A1480LS-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEA1480LSCat.No.:HY-181482分⼦式:C₃₀H₂₅F₃N₆O分⼦量:542.55作⽤靶点:DAGL作⽤通路:MetabolicEnzyme/Protease储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性A1480LS⼀种外周限制性、⼝服有效的DAGLα和DAGLβ的共价且不可逆抑制剂，在⼈靶点中的IC50值分别为6nM和4nM，在⼩⿏、⼤⿏、⽝、猴和⼈体系中的IC50均≤15nM。A1480LS可降低2-花⽣四烯酸⽢油酯、花⽣四烯酸以及环氧合酶和脂氧合酶衍⽣的类⼆⼗烷酸⽔平。A1480LS可抑制外周坐⾻神经中由损伤诱导的2-花⽣四烯酸⽢油酯和花⽣四烯酸的⽣成，并抑制⾼阈值和宽动态范样⾓神经元对机械刺激的反应。A1480LS可减轻炎症性疼痛、神经性疼痛和化疗诱导的周神经病⼤⿏模型的疼痛⾏为[1]。IC50&TargetDAGLαDAGLβ体内研究A1480LS(1-20mg/kg;p.o.;twice)producesdose-dependentreliefofmechanicalallodyniainaratCFAinflammatorypainmodelbyinhibitingperipheralDAGLwithoutalteringbrain2-AGlevels,withanED50of7.7mg/kg[1].A1480LS(15,20mg/kg;p.o.)rapidlyalleviatesandcontinuouslyinhibitspaclitaxel-inducedmechanicalhyperalgesiainratsduring5consecutivedaysofadministration.ItalsoreversesandmaintainsCCI-inducedmechanicalallodyniainratstotheshamoperationlevel,whilerestoringtheinjury-inducedelevatedlevelsof2-AGandAAinthesciaticnervetonormal,withoutaffectingthelevelsoftheselipidsinthebrain[1].A1480LS(1mg/kg;i.v.)selectivelyinhibitstheactivityofHTandWDR-likedorsalhornneuronsinanesthetizedCCIratswithoutalteringtheactivityofLTMRs,indicatingthatitsuppressesspinalnociceptivesensoryinput[1].A1480LS(8-30mg/kg;p.o.)doesnotmodulatePTZ-inducedseizuresusceptibilityorbrain2-AGlevelsinrats,iswelltoleratedin*Rattusnorvegicus*rats,withonlymild,transientreductioninabdominalmuscletoneobservedinsomeanimals;thesefindingsindicatethatitposesnocentralnervoussystemepileptogenicrisk[1].1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEAnimalModel:SpragueDawley(male,176-206g,intraplantarCFAinjection)[1]Dosage:1mg/kg;2.5mg/kg;5mg/kg;10mg/kg;20mg/kgAdministration:p.o.;2doses(2hbeforeCFA,24hafterCFA)Result:Increasedmechanicalwithdrawalthresholdsdose-dependently4haftertheseconddose,withanED50of7.7mg/kg.Achievedaveragebloodconcentrationsof1.1μM(freeplasmaconcentrations=1.5nM)at20mg/kg,withanEC50of0.22μMtosuppressallodynia.InhibitedkidneyDAGLβactivityandreducedkidney2-AGconcentrationsdose-dependently.CausedpartialbrainDAGLα/βinhibitionat10and20mg/kgwithoutbrain2-AGdepletion.AnimalModel:SpragueDawley(male,intraperitonealpaclitaxelinjection1mg/kgdailyfor5consecutivedays)[1]Dosage:15mg/kg(singledose;establishedallodynia);15mg/kg(repeateddosing;maintainedanti-allodyniceffects)Administration:p.o.;singledoseonday7;oncedailyfor5days(days15-18)Result:Attenuatedestablishedmechanicalallodynia4hpost-doseonday7withasingle15mg/kgoraldose.Maintainedsignificantanti-allodyniceffectsover5dayswithrepeatedonce-dailydosingof15mg/kgfromdays15-18,comparabletoduloxetine.AnimalModel:SpragueDawley(male,200-220gatsurgery;233-289gatdosing,chronicconstrictioninjuryofleftcommonsciaticnerve)[1]Dosage:20mg/kg(repeateddosing;allodyniareversal);20mg/kg(singledose;lipidanalysis)Administration:p.o.;oncedailyfor5days(days14-18);singledose14dayspost-CCIResult:ReversedallodyniaandrestoredvonFreythresholdstoshamlevelswithrepeated20mg/kgdosing,withefficacycomparabletonaproxenandpregabalin.Reduced2-AGandnormalizedAAconcentrationsininjuredsciaticnerveswithasingle20mg/kgdose,afterCCIcauseda7-foldincreasein2-AGand2-foldincreaseinAA.AnimalModel:SpragueDawley(male,250-315g,chronicconstrictioninjuryofleftsciaticnerve,rightjugularveincatheterimplantation)[1]Dosage:0.1mg/kg;0.3mg/kg;1mg/kg2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEAdministration:i.v.;singlebolusafterbaselinevehiclerecordingResult:Produceddose-dependentmodulationofhigh-threshold(HT)andwidedynamicrange-like(WDR-like)single-unitresponses,withrobustsuppressionat1mg/kg.Didnotmodulatelow-thresholdmechanoreceptor(LTMR)single-unitactivityat1mg/kg.AnimalModel:SpragueDawley(male,208-263g,subcutaneouspentylenetetrazoleinjection80mg/kg)[1]Dosage:8mg/kg;16mg/kg;30mg/kgAdministration:p.o.;singledose4hpre-PTZResult:Didnotalterconvulsionlatencyoroccurrenceatanytesteddose.Didnotchangebrain2-AGlevelsfollowingadministration.REFERENCES[1].TufailYZ,etal.Suppressionofpaintransmissionandbehaviorbyinhibitionofperipheraldiacylglycerolmetabolism.CellChem