Endocannabinoid_System_內(nèi)源性大麻素系統(tǒng)課件

1、Targeting the endocannabinoid system: to enhance or reduce?Vincenzo DMNATURE REVIEWS | DRUG DISCOVERY, 2008IntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonistsCannabinoidEndocannabinoidAnandamide2-AGRecptorsCannab

2、inoid receptorsCB1 and CB2Anandamide has highest affinity2-AG has highest efficacyRetrograde signallingOther “receptors” of cannabinoidTRPV1GPR55 ?PPARs-alpha/beta ?Development strategy of endocannabinoid system targeted drugDirect agonist Tetrahydrocannabinol and its synthetic analoguesNewer drugs

3、Inhibiter of endocannabinoid degradationSA-47URB597Cannabinoid receptor (CB) antagonistsRimonabantTaranabantIntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonistsNOTEMeasurementAmounts of endocannabinoid Changes of

4、endocannabinoid level Bidirectional or paradox effectsPositive and negativeProtective and worseningMultiple functional outcomeEatting disordersPhysiological conditionAdaptive responseIntake of foodCope with the lack of foodPathological conditionDisrupted orexigenic mechanismNeural-diseaseNeurodegene

5、rationParlinsons diseaseBeta-amyloid-cytotoxicity (AD)Multiple sclerosis and experimental allergic encephalitisAmyotrophic lateral sclerosisAnxiety and depressionPain and inflammationRoles of endocannabinoids duringcentral neuroinflammationRoles of endocannabinoids duringperipheral neuroinflammation

6、Liver disease and osteoporosisDetrimental and beneficial effects of CB1 and CB2 respectivelyHepatic pathologyChronic upregulation of endocannabinoid levelOsteoporosisOther diseasesCancerGastrointestinal inflammationIntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect a

7、gonistsTherapeutic use of inverse agonists/antagonistsInhibitors of catabolismInhibitors of catabolismFAAH blockers more selective towards anandamideMAGLs blockers specific for 2-AGURB-597 (preclinical stage)AA-5-HT (also antagonize TRPV1)SA-72Endocannabinoid indirect agonists: inhibitors of FAAH an

8、d MAGLInhibitors of cellular reuptakeInhibitorsAromatic acylamide derivativesAM404VDM-11OMDM-1 and OMDM-2etc.Carbamoyl-tetrazoles LY2183240 (also a FAAH inhibitor)Potential indications tested in animal modelsEndocannabinoid indirect agonists: Inhibitors of cellular reuptakePotential disadvantages“Of

9、f-targets” problem (FAAH inhibitors)Raise non-endocannabinoid substratesActivate non-cannabinoid receptors (e.g. TRPV1)AA-5-HT: FAAH/TRPV1 blocker (strategy)Some reuptake inhibitor (AM404)“No develop” (MAGLs inhibitors)“Time point” problem (Reuptake inhibitors)IntroductionUps and downs of endocannab

10、inoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonistsCB1 receptor antagonistsCatabolism disordersNicotine or Cocaine dependenceOthersCB2 receptor antagonistsAnti-inflammatoryAnti-allergicAutoimmune disordersCB1 receptor antagonists/inverse agonists in c

11、linical trials (not all)CB2 receptor antagonists/inverse agonists in preclinical trials (not all)Potential disadvantagesNot as neutral antagonists but as inverse agonists (non-specific effects)Interference with unconcerned disorders in which endocannabinoids might have protective effectsPerhaps no other signalling system discovered during the past 15 years is raising as many expectations for the development of new therapeutic drugs, encompassing such a