Endocannabinoid System 内源性大麻素系统

Targetingtheendocannabinoidsystem:toenhanceorreduce?VincenzoDMNATUREREVIEWS|DRUGDISCOVERY,2008IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsCannabinoidEndocannabinoidAnandamide2-AGRecptorsCannabinoidreceptorsCB1andCB2Anandamidehashighestaffinity2-AGhashighestefficacyRetrogradesignallingOther“receptors”ofcannabinoidTRPV1GPR55???PPARs-alpha/beta???DevelopmentstrategyofendocannabinoidsystemtargeteddrugDirectagonist×TetrahydrocannabinolanditssyntheticanaloguesNewerdrugs√InhibiterofendocannabinoiddegradationSA-47URB597Cannabinoidreceptor(CB)antagonistsRimonabantTaranabantIntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsNOTEMeasurementAmountsofendocannabinoid×Changesofendocannabinoidlevel√BidirectionalorparadoxeffectsPositiveandnegativeProtectiveandworseningMultiplefunctionaloutcomeEattingdisordersPhysiologicalconditionAdaptiveresponseIntakeoffoodCopewiththelackoffoodPathologicalconditionDisruptedorexigenicmechanismNeural-diseaseNeurodegenerationParlinson’sdiseaseBeta-amyloid-cytotoxicity(AD)MultiplesclerosisandexperimentalallergicencephalitisAmyotrophiclateralsclerosisAnxietyanddepressionPainandinflammationRolesofendocannabinoidsduringcentralneuroinflammationRolesofendocannabinoidsduringperipheralneuroinflammationLiverdiseaseandosteoporosisDetrimentalandbeneficialeffectsofCB1andCB2respectivelyHepaticpathologyChronicupregulationofendocannabinoidlevelOsteoporosisOtherdiseasesCancerGastrointestinalinflammationIntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsInhibitorsofcatabolismInhibitorsofcatabolismFAAHblockers–moreselectivetowardsanandamideMAGLsblockers–specificfor2-AGURB-597(preclinicalstage)AA-5-HT(alsoantagonizeTRPV1)SA-72Endocannabinoidindirectagonists:inhibitorsofFAAHandMAGLInhibitorsofcellularreuptakeInhibitorsAromaticacylamidederivativesAM404VDM-11OMDM-1andOMDM-2etc.Carbamoyl-tetrazolesLY2183240(alsoaFAAHinhibitor)PotentialindicationstestedinanimalmodelsEndocannabinoidindirectagonists:InhibitorsofcellularreuptakePotentialdisadvantages“Off-targets”problem(FAAHinhibitors)Raisenon-endocannabinoidsubstratesActivatenon-cannabinoidreceptors(e.g.TRPV1)AA-5-HT:FAAH/TRPV1blocker(strategy)Somereuptakeinhibitor(AM404)“Nodevelop”(MAGLsinhibitors)“Timepoint”problem(Reuptakeinhibitors)IntroductionUpsanddownsofendocannabinoidsindiseaseTherapeuticuseofindirectagonistsTherapeuticuseofinverseagonists/antagonistsCB1receptorantagonistsCatabolismdisordersNicotineorCocainedependenceOthersCB2receptorantagonistsAnti-inflammatoryAnti-allergicAutoimmunedisordersCB1receptorantagonists/inverseagonistsinclinicaltrials(notall)CB2receptorantagonists/inverseagonistsinpreclinicaltrials(notall)PotentialdisadvantagesNotasneutralantagonistsbutasinverseagonists(non-specificeffects)InterferencewithunconcerneddisordersinwhichendocannabinoidsmighthaveprotectiveeffectsPerhapsnoothersignallingsystemdiscoveredduringthepast15yearsisraisingasmanyexpectationsforthedevelopmentofnewtherapeuticdrugs,encompassingsuchavarietyofpathologicalconditions,targetingsomanydifferentorgansandtissues,andusingsuchawiderangeofpotentialstrategiesfortreatment,astheendocannabinoidsystem.