内源性大麻素系统-课件

IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction1CannabinoidEndocannabinoidAnandamide2-AGCannabinoid2内源性大麻素系统--课件3RecptorsCannabinoidreceptorsCB1andCB2Anandamidehashighestaffinity2-AGhashighestefficacyRetrogradesignallingOther“receptors”ofcannabinoidTRPV1GPR55???PPARs-alpha/beta???RecptorsCannabinoidreceptors4内源性大麻素系统--课件5DevelopmentstrategyofendocannabinoidsystemtargeteddrugDirectagonist×TetrahydrocannabinolanditssyntheticanaloguesNewerdrugs√InhibiterofendocannabinoiddegradationSA-47URB597Cannabinoidreceptor(CB)antagonistsRimonabantTaranabantDevelopmentstrategyofendoca6IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction7NOTEMeasurementAmountsofendocannabinoid×Changesofendocannabinoidlevel√BidirectionalorparadoxeffectsPositiveandnegativeProtectiveandworseningMultiplefunctionaloutcomeNOTEMeasurement8EattingdisordersPhysiologicalconditionAdaptiveresponseIntakeoffoodCopewiththelackoffoodPathologicalconditionDisruptedorexigenicmechanismEattingdisordersPhysiological9Neural-diseaseNeurodegenerationParlinson’sdiseaseBeta-amyloid-cytotoxicity(AD)MultiplesclerosisandexperimentalallergicencephalitisAmyotrophiclateralsclerosisAnxietyanddepressionPainandinflammationNeural-diseaseNeurodegeneratio10内源性大麻素系统--课件11Rolesofendocannabinoidsduring

centralneuroinflammationRolesofendocannabinoidsduri12Rolesofendocannabinoidsduring

peripheralneuroinflammationRolesofendocannabinoidsduri13LiverdiseaseandosteoporosisDetrimentalandbeneficialeffectsofCB1andCB2respectivelyHepaticpathologyChronicupregulationofendocannabinoidlevelOsteoporosisLiverdiseaseandosteoporosis14OtherdiseasesCancerGastrointestinalinflammationOtherdiseases15IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction16InhibitorsofcatabolismInhibitorsofcatabolismFAAHblockers–moreselectivetowardsanandamideMAGLsblockers–specificfor2-AGURB-597(preclinicalstage)AA-5-HT(alsoantagonizeTRPV1)SA-72InhibitorsofcatabolismInhibi17Endocannabinoidindirectagonists:inhibitorsofFAAHandMAGLEndocannabinoidindirectagoni18InhibitorsofcellularreuptakeInhibitorsAromaticacylamidederivativesAM404VDM-11OMDM-1andOMDM-2etc.Carbamoyl-tetrazolesLY2183240(alsoaFAAHinhibitor)PotentialindicationstestedinanimalmodelsInhibitorsofcellularreuptak19Endocannabinoidindirectagonists:InhibitorsofcellularreuptakeEndocannabinoidindirectagoni20Potentialdisadvantages“Off-targets”problem(FAAHinhibitors)Raisenon-endocannabinoidsubstratesActivatenon-cannabinoidreceptors(e.g.TRPV1)AA-5-HT:FAAH/TRPV1blocker(strategy)Somereuptakeinhibitor(AM404)“Nodevelop”(MAGLsinhibitors)“Timepoint”problem(Reuptakeinhibitors)Potentialdisadvantages“Off-ta21IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction22CB1receptorantagonistsCatabolismdisordersNicotineorCocainedependenceOthersCB2receptorantagonistsAnti-inflammatoryAnti-allergicAutoimmunedisordersCB1receptorantagonists23CB1receptorantagonists/inverseagonistsinclinicaltrials(notall)CB1receptorantagonists/inver24CB2receptorantagonists/inverseagonistsinpreclinicaltrials(notall)CB2receptorantagonists/inver25PotentialdisadvantagesNotasneutralantagonistsbutasinverseagonists(non-specificeffects)InterferencewithunconcerneddisordersinwhichendocannabinoidsmighthaveprotectiveeffectsPotentialdisadvantagesNotas26ENDEND27Perhapsnoothersignallingsystemdiscoveredduringthepast15yearsisraisingasmanyexpectationsforthedevelopmentofnewtherapeuticdrugs,encompassingsuc