Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEMethocinnamoxCat.No.:HY-135698CASNo.:117339-76-1Synonyms:M-CAM分?式:C??H??N?O?分?量:484.59作?靶點(diǎn):OpioidReceptor作?通路:GPCR/GProtein;NeuronalSignaling儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性Methocinnamox(M-CAM)?種選擇性的、長(zhǎng)效的μ-阿?受體(MOR)拮抗劑，其Ki為0.6nM。Methocinnamox與MOR的結(jié)合持續(xù)時(shí)間極長(zhǎng)，這種長(zhǎng)效性于其與MOR正構(gòu)位點(diǎn)的?共價(jià)結(jié)合，導(dǎo)致受體功能持續(xù)阻斷，需依賴新受體合成才能恢復(fù)功能。Methocinnamox對(duì)κ-阿?受體(KOR)(Ki=4.9nM)和δ-阿?受體(DOR)(Ki=2.2nM)均有可逆性拮抗作?，并且對(duì)這些受體不表現(xiàn)出內(nèi)在激動(dòng)劑活性。Methocinnamox可?于逆轉(zhuǎn)和預(yù)防阿?過量和使?障礙。IC50&TargetμOpioidReceptor/MORκOpioidReceptor/KORδOpioidReceptor/DOR0.6nM(Ki)4.9nM(Ki)2.2nM(Ki)體外研究Methocinnamoxbindsverytightlytotheμreceptorinthemousebraintissueandhasanextremelyslowdissociationrate,butithasnoeffectonthebindingsitesoftheδandκreceptors[3].MethocinnamoxinsurmountableandpseudoirreversibleblockstheinhibitoryeffectsofDAMGO(HY-P0210),psychoactivecompoundandmorphineontheaccumulationofcAMPinHEK293cellsthathavebeentransfectedwithhumanμ-opioidreceptor[3].體內(nèi)研究Methocinnamox(10mg/kg,s.c.,singledose)effectivelycounteractsavarietyofeffectsmediatedbymorphine(analgesia,respiratorydepression,gastrointestinalinhibition,andchangesinbodytemperature)inrats,andtheantagonisticeffectpersistsformorethantwoweeksafterasingleadministration[1].Methocinnamox(0.0001-10mg/kg,i.v.or10mg/kg,i.v.ands.c,singledose)effectivelyreversesandprotectstherespiratorydepressioncausedbypsychoactivecompoundinrats[2].Methocinnamox(0.32mg/kg,s.c.,singledose,oronceevery12daysfor5doses;0.032mg/kg,oncedaily1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEfor21days)reducestheself-administrationbehaviorofopioids,butithasnoeffectontheself-administrationoftheresponsetofoodinrhesusmonkeys[3].AnimalModel:Pawinflammationandmechanicalsensitivity,gastrointestinaltransitandphysicaldependenceandwithdrawalmodelestablishedinmaleSprague-Dawleyrats[1]Dosage:10mg/kgAdministration:Subcutaneousinjection(s.c.),singledoseResult:Significantlyreducedtheanalgesiceffectofmorphineonpawinflammationandthisantagonisticeffectpersistedforatleast15days.Blockedtheincreaseinbodytemperaturecausedbymorphine,withtheeffectlastingformorethan15days.Completelyblockedtheinhibitoryeffectofmorphineongastrointestinalperistalsisuntil21days.Didnotresultinalongerormoreseverewithdrawalsyndrome.AnimalModel:ReversalofpsychoactivecompoundassayestablishedinadultmaleSprague-Dawleyrats[2]Dosage:0.0001,0.001,0.01,0.1,1,10mg/kg(i.v.)and10mg/kg(i.v.)and(s.c)Administration:Intravenousinjection(i.v.)andsubcutaneousinjection(s.c.),singledoseResult:Dose-dependentlyrapidlyreversedsevererespiratorydepression.Providelong-lastingprotectionandeffectivelypreventthe"re-anesthesia"phenomenonthatoccursafterrescue.Exhibitedasignificantlylongerdurationofactionwhenadministeredsubcutaneously(s.c.)comparedtointravenous(i.v.)administrationatthesamedose.AnimalModel:Self-Administrationmodelestablishedinrhesusmonkeys[3]Dosage:0.032mg/kgand0.32mg/kgAdministration:Subcutaneousinjection(s.c.),singledose,oronceevery12daysfor5doses(0.32mg/kg);oncedailyfor21days(0.032mg/kg)Result:Effectivelyandselectivelyblockedthereinforcingeffects(euphoria)ofopioidagent.Reducedtherelativereinforcingvalueofopioiddrugs,makingnon-drugrewards(suchasfood)moreattractive.Didnotimpairadvancedcognitivefunctionssuchasworkingmemoryorattention.hadnosignificanteffectonthecardiovascularsystemandbodytemperatureregulationat3.2mg/kg.REFERENCES2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE[1].GerakLR,etal.MethocinnamoxProducesLong-LastingAntagonismoftheBehavioralEffectsofμ-OpioidReceptorAgonistsbutNotProlongedPrecipitatedWithdrawalinRats.JPharmacolExpTher.2019Nov;371(2):507-516.[2].JimenezVMJr,CastanedaG,FranceCP.MethocinnamoxReversesandPreventsFentanyl-InducedVentilatoryDepressioninRats.JPharmacolExpTher.2021Apr;377(1):29-38.[3].MaguireDR,FranceCP.Behavioralpharmacologyofmethocinnamox:Apotentialnewtreatmentforopioidoverdoseandopioidusedisorder.JExpAnalBehav.2023Mar