EnannabinoidSystem内源性大麻素系统

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1、Targetingtheendocannabinoidsystem:toenhanceorreduce?VincenzoDMNATUREREVIEWS

2、DRUGDISCOVERY,2008IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsCannabinoidEndocannabinoidAnandamide2-AGRecpt

3、orsCannabinoidreceptorsCB1andCB2Anandamidehashighestaffinity2-AGhashighestefficacyRetrogradesignallingOther“receptors”ofcannabinoidTRPV1GPR55???PPARs-alpha/beta???DevelopmentstrategyofendocannabinoidsystemtargeteddrugDirectagonist×Tetrahydrocannabinolanditssyntheti

4、canaloguesNewerdrugs√InhibiterofendocannabinoiddegradationSA-47URB597Cannabinoidreceptor(CB)antagonistsRimonabantTaranabantIntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsNOTEMeasurementAm

5、ountsofendocannabinoid×Changesofendocannabinoidlevel√BidirectionalorparadoxeffectsPositiveandnegativeProtectiveandworseningMultiplefunctionaloutcomeEattingdisordersPhysiologicalconditionAdaptiveresponseIntakeoffoodCopewiththelackoffoodPathologicalconditionDisrupted

6、orexigenicmechanismNeural-diseaseNeurodegenerationParlinson’sdiseaseBeta-amyloid-cytotoxicity(AD)MultiplesclerosisandexperimentalallergicencephalitisAmyotrophiclateralsclerosisAnxietyanddepressionPainandinflammationRolesofendocannabinoidsduringcentralneuroinflamma

7、tionRolesofendocannabinoidsduringperipheralneuroinflammationLiverdiseaseandosteoporosisDetrimentalandbeneficialeffectsofCB1andCB2respectivelyHepaticpathologyChronicupregulationofendocannabinoidlevelOsteoporosisOtherdiseasesCancerGastrointestinalinflammationIntrodu

8、ctionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsInhibitorsofcatabolismInhibitorsofcatabolismFAAHblockers–moreselectivetowardsanandamideMAGLsblockers–specificfor2-AGURB-597(preclinicalstage)AA-5-H

9、T(alsoantagonizeTRPV1)SA-72Endocannabinoidindirectagonists:inhibitorsofFAAHandMAGLInhibitorsofcellularreuptakeInhibitorsAromaticacylamidederivati