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Targetingtheendocannabinoidsystem:

toenhanceorreduce?VincenzoDMNATUREREVIEWS|DRUGDISCOVERY,2008Targetingtheendocannabinoid1IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction2CannabinoidEndocannabinoidAnandamide2-AGCannabinoid3EndocannabinoidSystem內源性大麻素系統(tǒng)課件4RecptorsCannabinoidreceptorsCB1andCB2Anandamidehashighestaffinity2-AGhashighestefficacyRetrogradesignallingOther“receptors”ofcannabinoidTRPV1GPR55???PPARs-alpha/beta???RecptorsCannabinoidreceptors5EndocannabinoidSystem內源性大麻素系統(tǒng)課件6DevelopmentstrategyofendocannabinoidsystemtargeteddrugDirectagonist×TetrahydrocannabinolanditssyntheticanaloguesNewerdrugs√InhibiterofendocannabinoiddegradationSA-47URB597Cannabinoidreceptor(CB)antagonistsRimonabantTaranabantDevelopmentstrategyofendoca7IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction8NOTEMeasurementAmountsofendocannabinoid×Changesofendocannabinoidlevel√BidirectionalorparadoxeffectsPositiveandnegativeProtectiveandworseningMultiplefunctionaloutcomeNOTEMeasurement9EattingdisordersPhysiologicalconditionAdaptiveresponseIntakeoffoodCopewiththelackoffoodPathologicalconditionDisruptedorexigenicmechanismEattingdisordersPhysiological10Neural-diseaseNeurodegenerationParlinson’sdiseaseBeta-amyloid-cytotoxicity(AD)MultiplesclerosisandexperimentalallergicencephalitisAmyotrophiclateralsclerosisAnxietyanddepressionPainandinflammationNeural-diseaseNeurodegeneratio11EndocannabinoidSystem內源性大麻素系統(tǒng)課件12Rolesofendocannabinoidsduring

centralneuroinflammationRolesofendocannabinoidsduri13Rolesofendocannabinoidsduring

peripheralneuroinflammationRolesofendocannabinoidsduri14LiverdiseaseandosteoporosisDetrimentalandbeneficialeffectsofCB1andCB2respectivelyHepaticpathologyChronicupregulationofendocannabinoidlevelOsteoporosisLiverdiseaseandosteoporosis15OtherdiseasesCancerGastrointestinalinflammationOtherdiseases16IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction17InhibitorsofcatabolismInhibitorsofcatabolismFAAHblockers–moreselectivetowardsanandamideMAGLsblockers–specificfor2-AGURB-597(preclinicalstage)AA-5-HT(alsoantagonizeTRPV1)SA-72InhibitorsofcatabolismInhibi18Endocannabinoidindirectagonists:inhibitorsofFAAHandMAGLEndocannabinoidindirectagoni19InhibitorsofcellularreuptakeInhibitorsAromaticacylamidederivativesAM404VDM-11OMDM-1andOMDM-2etc.Carbamoyl-tetrazolesLY2183240(alsoaFAAHinhibitor)PotentialindicationstestedinanimalmodelsInhibitorsofcellularreuptak20Endocannabinoidindirectagonists:InhibitorsofcellularreuptakeEndocannabinoidindirectagoni21Potentialdisadvantages“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-ta22IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction23CB1receptorantagonistsCatabolismdisordersNicotineorCocainedependenceOthersCB2receptorantagonistsAnti-inflammatoryAnti-allergicAutoimmunedisordersCB1receptorantagonists24CB1receptorantagonists/inverseagonistsinclinicaltrials(notall)CB1receptorantagonists/inver25CB2receptorantagonists/inverseagonistsinpreclinicaltrials(notall)CB2receptorantagonists/inver26PotentialdisadvantagesNotasneutralantagonistsbutasinverseagonists(non-specificeffects)InterferencewithunconcerneddisordersinwhichendocannabinoidsmighthaveprotectiveeffectsPotentialdisadvantagesNotas27Perhapsnoothersignallingsystemdiscoveredduringthepast15yearsisraisingasmanyexpectationsforthedevelopmentofnewtherapeuticdrugs,encompassingsuchavarietyofpathologicalconditions,targetingsomanydifferentorgansandtissues,andusingsuchawiderangeofpotentialstrategiesfortreatment,astheendocannabinoidsystem.Perhapsnoothersignallingsy28Targetingtheendocannabinoidsystem:

toenhanceorreduce?VincenzoDMNATUREREVIEWS|DRUGDISCOVERY,2008Targetingtheendocannabinoid29IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction30CannabinoidEndocannabinoidAnandamide2-AGCannabinoid31EndocannabinoidSystem內源性大麻素系統(tǒng)課件32RecptorsCannabinoidreceptorsCB1andCB2Anandamidehashighestaffinity2-AGhashighestefficacyRetrogradesignallingOther“receptors”ofcannabinoidTRPV1GPR55???PPARs-alpha/beta???RecptorsCannabinoidreceptors33EndocannabinoidSystem內源性大麻素系統(tǒng)課件34DevelopmentstrategyofendocannabinoidsystemtargeteddrugDirectagonist×TetrahydrocannabinolanditssyntheticanaloguesNewerdrugs√InhibiterofendocannabinoiddegradationSA-47URB597Cannabinoidreceptor(CB)antagonistsRimonabantTaranabantDevelopmentstrategyofendoca35IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction36NOTEMeasurementAmountsofendocannabinoid×Changesofendocannabinoidlevel√BidirectionalorparadoxeffectsPositiveandnegativeProtectiveandworseningMultiplefunctionaloutcomeNOTEMeasurement37EattingdisordersPhysiologicalconditionAdaptiveresponseIntakeoffoodCopewiththelackoffoodPathologicalconditionDisruptedorexigenicmechanismEattingdisordersPhysiological38Neural-diseaseNeurodegenerationParlinson’sdiseaseBeta-amyloid-cytotoxicity(AD)MultiplesclerosisandexperimentalallergicencephalitisAmyotrophiclateralsclerosisAnxietyanddepressionPainandinflammationNeural-diseaseNeurodegeneratio39EndocannabinoidSystem內源性大麻素系統(tǒng)課件40Rolesofendocannabinoidsduring

centralneuroinflammationRolesofendocannabinoidsduri41Rolesofendocannabinoidsduring

peripheralneuroinflammationRolesofendocannabinoidsduri42LiverdiseaseandosteoporosisDetrimentalandbeneficialeffectsofCB1andCB2respectivelyHepaticpathologyChronicupregulationofendocannabinoidlevelOsteoporosisLiverdiseaseandosteoporosis43OtherdiseasesCancerGastrointestinalinflammationOtherdiseases44IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction45InhibitorsofcatabolismInhibitorsofcatabolismFAAHblockers–moreselectivetowardsanandamideMAGLsblockers–specificfor2-AGURB-597(preclinicalstage)AA-5-HT(alsoantagonizeTRPV1)SA-72InhibitorsofcatabolismInhibi46Endocannabinoidindirectagonists:inhibitorsofFAAHandMAGLEndocannabinoidindirectagoni47InhibitorsofcellularreuptakeInhibitorsAromaticacylamidederivativesAM404VDM-11OMDM-1andOMDM-2etc.Carbamoyl-tetrazolesLY2183240(alsoaFAAHinhibitor)PotentialindicationstestedinanimalmodelsInhibitorsofcellularreuptak48Endocannabinoidindirectagonists:InhibitorsofcellularreuptakeEndocannabinoidindirectagoni49Potentialdisadvantages“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-ta50IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsIntroduction51CB1receptorantagonistsCatabolismdisordersNicotineorCocainedependenceOthersCB2receptor

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