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1、Targeting the endocannabinoid system: to enhance or reduce?Vincenzo DMNATURE REVIEWS | DRUG DISCOVERY, 2008nIntroductionnUps and downs of endocannabinoids in diseasenTherapeutic use of indirect agonistsnTherapeutic use of inverse agonists/antagonistsnCannabinoidnEndocannabinoid nAnandamide n2-AGRecp
2、torsnCannabinoid receptors nCB1 and CB2 nAnandamide has highest affinity n2-AG has highest efficacy nRetrograde signalling nOther “receptors” of cannabinoid nTRPV1 nGPR55 ? nPPARs-alpha/beta ?Development strategy of endocannabinoid system targeted drugnDirect agonist nTetrahydrocannabinol and its sy
3、nthetic analogues nNewer drugs nInhibiter of endocannabinoid degradation nSA-47 nURB597 nCannabinoid receptor (CB) antagonists nRimonabant nTaranabantnIntroductionnUps and downs of endocannabinoids in diseasenTherapeutic use of indirect agonistsnTherapeutic use of inverse agonists/antagonistsNOTEnMe
4、asurement nAmounts of endocannabinoid nChanges of endocannabinoid level nBidirectional or paradox effects nPositive and negative nProtective and worsening nMultiple functional outcomeEatting disordersnPhysiological condition nAdaptive response nIntake of food nCope with the lack of foodnPathological
5、 condition nDisrupted orexigenic mechanismNeural-diseasenNeurodegeneration nParlinsons disease nBeta-amyloid-cytotoxicity (AD) nMultiple sclerosis and experimental allergic encephalitis nAmyotrophic lateral sclerosis nAnxiety and depression nPain and inflammationRoles of endocannabinoids during cent
6、ral neuroinflammationRoles of endocannabinoids during peripheral neuroinflammationLiver disease and osteoporosisnDetrimental and beneficial effects of CB1 and CB2 respectivelynHepatic pathology nChronic upregulation of endocannabinoid levelnOsteoporosisOther diseasesnCancernGastrointestinal inflamma
7、tionnIntroductionnUps and downs of endocannabinoids in diseasenTherapeutic use of indirect agonistsnTherapeutic use of inverse agonists/antagonistsInhibitors of catabolismnInhibitors of catabolism nFAAH blockers more selective towards anandamide nMAGLs blockers specific for 2-AGnURB-597 (preclinical
8、 stage) nAA-5-HT (also antagonize TRPV1) nSA-72Endocannabinoid indirect agonists: inhibitors of FAAH and MAGLInhibitors of cellular reuptakenInhibitors nAromatic acylamide derivatives nAM404 nVDM-11 nOMDM-1 and OMDM-2 netc. nCarbamoyl-tetrazoles nLY2183240 (also a FAAH inhibitor) nPotential indicati
9、ons tested in animal modelsEndocannabinoid indirect agonists: Inhibitors of cellular reuptakePotential disadvantagesn“Off-targets” problem (FAAH inhibitors) nRaise non-endocannabinoid substrates nActivate non-cannabinoid receptors (e.g. TRPV1) nAA-5-HT: FAAH/TRPV1 blocker (strategy) nSome reuptake i
10、nhibitor (AM404) n“No develop” (MAGLs inhibitors) n“Time point” problem (Reuptake inhibitors)nIntroductionnUps and downs of endocannabinoids in diseasenTherapeutic use of indirect agonistsnTherapeutic use of inverse agonists/antagonistsnCB1 receptor antagonists nCatabolism disorders nNicotine or Coc
11、aine dependence nOthers nCB2 receptor antagonists nAnti-inflammatory nAnti-allergic nAutoimmune disordersCB1 receptor antagonists/inverse CB1 receptor antagonists/inverse agonists in agonists in clinicalclinical trials (not all) trials (not all)CB2 receptor antagonists/inverse CB2 receptor antagonis
12、ts/inverse agonists in agonists in preclinicalpreclinical trials (not all) trials (not all)Potential disadvantagesnNot as neutral antagonists but as inverse agonists (non-specific effects)nInterference with unconcerned disorders in which endocannabinoids might have protective effectsPerhaps no other
13、 signalling system discovered during the past 15 years is raising as many expectations for the development of new therapeutic drugs, encompassing such a variety of pathological conditions, targeting so many different organs and tissues, and using such a wide range of potential strategies for treatment, as the endocannabinoid system.
