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

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

2、cyRetrograde signallingOther “receptors” of cannabinoidTRPV1GPR55 ?PPARs-alpha/beta ?第4頁，共27頁。第5頁，共27頁。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頁，共27頁。IntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonists第7頁，共27頁。NOTEMeasurementAmounts of endocannabinoid Changes of endocannabinoid level Bidirectional or parad

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

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

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

7、seaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonists第16頁，共27頁。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頁，共27頁。En

8、docannabinoid indirect agonists: inhibitors of FAAH and MAGL第18頁，共27頁。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頁，共27頁。Endocannabinoid in

9、direct agonists: Inhibitors of cellular reuptake第20頁，共27頁。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頁，共27頁。IntroductionUps and downs of endocannabinoids in diseaseTherapeutic use of indirect agonistsTherapeutic use of inverse agonists/antagonists第22頁，共27頁。CB1 receptor antagonistsCatabolism disordersNicotine or Cocaine dependenceOthersCB2 receptor ant

11、agonistsAnti-inflammatoryAnti-allergicAutoimmune disorders第23頁，共27頁。CB1 receptor antagonists/inverse agonists in clinical trials (not all)第24頁，共27頁。CB2 receptor antagonists/inverse agonists in preclinical trials (not all)第25頁，共27頁。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頁，共27頁。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