EnannabinoidSystem内源性大麻素系统课件

1、IntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonists第1页，共27页。CannabinoidEndocannabinoidAnandamide2-AG第2页，共27页。第3页，共27页。RecptorsCannabinoid receptorsCB1 and CB2Anandamide has highest affinity2-AG has highest effica

2、cyRetrograde signallingOther “receptors” of cannabinoidTRPV1GPR55 ?PPARs-alpha/beta ?第4页，共27页。第5页，共27页。Development strategy of endocannabinoid system targeted drugDirect agonist Tetrahydrocannabinol and its synthetic analoguesNewer drugs Inhibiter of endocannabinoid degradationSA-47URB597Cannabinoid

3、 receptor (CB) antagonistsRimonabantTaranabant第6页，共27页。IntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonists第7页，共27页。NOTEMeasurementAmounts of endocannabinoid Changes of endocannabinoid level Bidirectional or parad

4、ox effectsPositive and negativeProtective and worseningMultiple functional outcome第8页，共27页。Eatting disordersPhysiological conditionAdaptive responseIntake of foodCope with the lack of foodPathological conditionDisrupted orexigenic mechanism第9页，共27页。Neural-diseaseNeurodegenerationParlinsons diseaseBe

5、ta-amyloid-cytotoxicity (AD)Multiple sclerosis and experimental allergic encephalitisAmyotrophic lateral sclerosisAnxiety and depressionPain and inflammation第10页，共27页。第11页，共27页。Roles of endocannabinoids duringcentral neuroinflammation第12页，共27页。Roles of endocannabinoids duringperipheral neuroinflamma

6、tion第13页，共27页。Liver disease and osteoporosisDetrimental and beneficial effects of CB1 and CB2 respectivelyHepatic pathologyChronic upregulation of endocannabinoid levelOsteoporosis第14页，共27页。Other diseasesCancerGastrointestinal inflammation第15页，共27页。IntroductionUps and downs of endocannabinoids in di

7、seaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonists第16页，共27页。Inhibitors of catabolismInhibitors of catabolismFAAH blockers more selective towards anandamideMAGLs blockers specific for 2-AGURB-597 (preclinical stage)AA-5-HT (also antagonize TRPV1)SA-72第17页，共27页。En

8、docannabinoid indirect agonists: inhibitors of FAAH and MAGL第18页，共27页。Inhibitors of cellular reuptakeInhibitorsAromatic acylamide derivativesAM404VDM-11OMDM-1 and OMDM-2etc.Carbamoyl-tetrazoles LY2183240 (also a FAAH inhibitor)Potential indications tested in animal models第19页，共27页。Endocannabinoid in

9、direct agonists: Inhibitors of cellular reuptake第20页，共27页。Potential disadvantages“Off-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 inhibito

10、rs)“Time point” problem (Reuptake inhibitors)第21页，共27页。IntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonists第22页，共27页。CB1 receptor antagonistsCatabolism disordersNicotine or Cocaine dependenceOthersCB2 receptor ant

11、agonistsAnti-inflammatoryAnti-allergicAutoimmune disorders第23页，共27页。CB1 receptor antagonists/inverse agonists in clinical trials (not all)第24页，共27页。CB2 receptor antagonists/inverse agonists in preclinical trials (not all)第25页，共27页。Potential disadvantagesNot as neutral antagonists but as inverse agon

12、ists (non-specific effects)Interference with unconcerned disorders in which endocannabinoids might have protective effects第26页，共27页。Perhaps 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 va