Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEJNJ16259685Cat.No.:HY-100407CASNo.:409345-29-5分?式:C??H??NO?分?量:325.4作?靶點:mGluR作?通路:GPCR/GProtein;NeuronalSignaling儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數據體外實驗DMSO:≥100mg/mL(307.31mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲備液1mM3.0731mL15.3657mL30.7314mL5mM0.6146mL3.0731mL6.1463mL10mM0.3073mL1.5366mL3.0731mL請根據產品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；?旦配成溶液，請分裝保存，避免反復凍融造成的產品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲存時，請在6個?內使?，-20°C儲存時，請在1個?內使?。體內實驗請根據您的實驗動物和給藥?式選擇適當的溶解?案。以下溶解?案都請先按照InVitro?式配制澄的儲備液，再依次添加助溶劑：(為保證實驗結果的可靠性，澄的儲備液可以根據儲存條件，適當保存；體內實驗的?作液，建議您現?現配，當天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過程中出現沉淀、析出現象，可以通過加熱和/或超聲的?式助溶)1.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.75mg/mL(8.45mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.75mg/mL(8.45mM);Clearsolution3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.75mg/mL(8.45mM);ClearsolutionBIOLOGICALACTIVITY?物活性JNJ16259685?種選擇性的mGlu1receptor拮抗劑，能夠濃度依賴性地抑制mGlu1的突觸的活化，IC50值為19nM。IC50&TargetmGluR119nM(IC50)體外研究JNJ16259685potentlyandcompletelyinhibitstheglutamate(30μM)-inducedincreaseinintracellularCa2+concentrationsattheratmGlu1areceptorwithanIC50valueof3.24±1.00nM.IC50valuesforCPCCOEtandBAY36-7620are17.8±10.3μMand161±38nM,respectively.ThepotencyofJNJ16259685inblockingglutamate(30μM)-inducedCa2+mobilizationatthehumanmGlu1areceptoris1.21±0.53nM(IC50n=3).JNJ16259685inhibitstheglutamate(3μM)-inducedriseinintracellularCa2+concentrationsattheratmGlu5areceptorwithanIC50valueof1.31±0.39μM(n=4).JNJ16259685blocksglutamate(3μM)-inducedCa2+mobilizationatthehumanmGlu5receptorwithanIC50of28.3±11.7μM(n=4).JNJ16259685doesnotexhibitagonistactivityatanyofthegroupImGlureceptors[3].體內研究JNJ16259685(0.125,0.25,0.5,1,2,4and8mg/kg,i.p)significantlyreducesthetimespentindiggingbehaviours(0.25-8mg/kg),threat(alldoses)andattack,incomparisonwithvehiclegroup[1].JNJ16259685(30mg/kg)producesveryminimaleffectsonlocomotoractivity.JNJ16259685dramaticallyreducesrearingbehavior,explorationofanovelenvironmentandleverpressingforafoodreward(rat:0.3mg/kg;mouse:1mg/kg).SubcutaneouslyadministeredJNJ16259685(30mg/kg)hasnoeffectonreflexivestartleresponsestoloudauditorystimuliorfootshockinmice[2].JNJ16259685exhibitshighpotenciesinoccupyingcentralmGlu1receptorsintheratcerebellumandthalamus(ED50=0.040and0.014mg/kg,respectively)[3].PROTOCOLAnimalMice[1]Administration[1][2]Ninegroupsofmiceareused.AnimalsarerandomLyallocatedtotwocontrolgroups(n=15each)receivingonlysalineorsaline(90%)plusDMSO(10%),andsevenexperimentalgroups(N=14-16each)receivingJNJ16259685injections.JNJ16259685isdilutedinsaline(90%)plusDMSO(10%)toprovideappropriatedosesforinjectionsandadministeredinsevendoses:0.125,0.25,0.5,1,2,4and8mg/kg.Thedosesarechosenonthebasisofrecentbehaviouralstudiesusingthiscompound.Drugorvehicleisinjectedintraperitoneallyinavolumeof10mL/kg.Rats[2]Thisprocedureisusedtomeasureovertbehavioral,neurologicalandautonomicresponsestothedrug2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEchallenge.Briefly,ratsarerandomLyseparatedintofourgroups(n=6),eachofwhichreceivesadifferentdose(0,3,10,or30mg/kg)ofJNJ16259685.Anexpertobserver,blindtothedrugtreatmentoftheanimals,assessesandscorestheanimalsat30,60,120,and240minpost-injection.Theanimalsareassessedforpassivity,bodyelevation,limbposition,limbtone,bodytone,gait,andpupilsize.Foreachofthesebehaviors,ascoreof0isassignedtoanimalsthatappeared“normal”,whereasscoresof±1,±2,or±3indicatedmild,moderate,orsevereincreases(+)ordecreases(?)fromnormality.Individualanimalsthatreceiveascoreof±2,orgreater,areconsideredtobesignificantlyeffectedonthemeasure.Adoseisconsideredtohaveasignificanteffectif3ormoreoftheanimalsreceiveascoreofgreaterthan±2.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.REFERENCES[1].NavarroJF,etal.JNJ16259685,aselectivemGlu1antagonist,suppressesisolation-inducedaggressioninmalemice.EurJPharmacol.2008May31;586(1-3):217-20.[2].HodgsonRA,etal.CharacterizationoftheselectivemGluR1antagonist,JNJ16259685,inrodentmodelsofmovementandcoordination.PharmacolBiochemBehav.2011Apr;98(2):181-7.[3].LavreysenH,etal.JNJ16259685,ahighlypotent,selectiveandsystemicallyactivemGlu1receptorantagonist.Neuropharmacology.2004Dec;47(7):961-72.[4].IFukunaga,etal.PotentandSpecificActionofthemGlu1AntagonistsYM-298198andJNJ16259685onSynapticTransmissioninRatCereb