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1、Targeting the endocannabinoid system: to enhance or reduce?VincenzoVincenzo DM DMNATURE REVIEWS | DRUG NATURE REVIEWS | DRUG DISCOVERY, 2008DISCOVERY, 2008nIntroductionnUps and downs of endocannabinoids in diseasenTherapeutic use of indirect agonistsnTherapeutic use of inverse agonists/antagonistsnC
2、annabinoidnEndocannabinoidnAnandamideAnandamiden2-AG2-AGRecptorsnCannabinoid receptorsnCB1 and CB2CB1 and CB2nAnandamide has highest affinityAnandamide has highest affinityn2-AG has highest efficacy2-AG has highest efficacynRetrograde signallingRetrograde signallingnOther “receptors” of cannabinoidn
3、TRPV1TRPV1nGPR55 ?GPR55 ?nPPARsPPARs-alpha/beta ?-alpha/beta ?Development strategy of endocannabinoid system targeted drugnDirect agonist nTetrahydrocannabinolTetrahydrocannabinol and its synthetic and its synthetic analoguesanaloguesnNewer drugs nInhibiter of endocannabinoid degradationInhibiter of
4、 endocannabinoid degradationn nSA-47SA-47n nURB597URB597nCannabinoid receptor (CB) antagonistsCannabinoid receptor (CB) antagonistsn nRimonabantRimonabantn nTaranabantTaranabantnIntroductionnUps and downs of endocannabinoids in diseasenTherapeutic use of indirect agonistsnTherapeutic use of inverse
5、agonists/antagonistsNOTEnMeasurementnAmounts of endocannabinoid Amounts of endocannabinoid nChanges of endocannabinoid level Changes of endocannabinoid level nBidirectional or paradox effectsnPositive and negativePositive and negativenProtective and worseningProtective and worseningnMultiple functio
6、nal outcomeMultiple functional outcomeEatting disordersnPhysiological conditionnAdaptive responseAdaptive responsen nIntake of foodIntake of foodn nCope with the lack of foodCope with the lack of foodnPathological conditionnDisrupted orexigenic mechanismDisrupted orexigenic mechanismNeural-diseasenN
7、eurodegenerationnParlinsonsParlinsons disease diseasenBeta-amyloid-cytotoxicity (AD)Beta-amyloid-cytotoxicity (AD)nMultiple sclerosis and experimental allergic Multiple sclerosis and experimental allergic encephalitisencephalitisnAmyotrophic lateral sclerosisAmyotrophic lateral sclerosisnAnxiety and
8、 depressionnPain and inflammationRoles of endocannabinoids duringRoles of endocannabinoids duringcentral central neuroinflammationneuroinflammationRoles of endocannabinoids duringRoles of endocannabinoids duringperipheral peripheral neuroinflammationneuroinflammationLiver disease and osteoporosisnDe
9、trimental and beneficial effects of CB1 and CB2 respectivelynHepatic pathologynChronic Chronic upregulationupregulation of endocannabinoid level of endocannabinoid levelnOsteoporosisOther diseasesnCancernGastrointestinal inflammationnIntroductionnUps and downs of endocannabinoids in diseasenTherapeu
10、tic use of indirect agonistsnTherapeutic use of inverse agonists/antagonistsInhibitors of catabolismnInhibitors of catabolismnFAAH blockers more selective towards FAAH blockers more selective towards anandamideanandamidenMAGLsMAGLs blockers specific for 2-AG blockers specific for 2-AGnURB-597 (precl
11、inical stage)nAA-5-HT (also antagonize TRPV1)nSA-72Endocannabinoid indirect agonists: Endocannabinoid indirect agonists: inhibitors of FAAH and MAGLinhibitors of FAAH and MAGLInhibitors of cellular reuptakenInhibitorsnAromatic Aromatic acylamideacylamide derivatives derivativesn nAM404AM404n nVDM-11
12、VDM-11n nOMDM-1 and OMDM-2OMDM-1 and OMDM-2n netc.etc.nCarbamoyl-tetrazolesCarbamoyl-tetrazoles n nLY2183240 (also a FAAH inhibitor)LY2183240 (also a FAAH inhibitor)nPotential indications tested in animal modelsEndocannabinoid indirect agonists: Endocannabinoid indirect agonists: Inhibitors of cellu
13、lar reuptakeInhibitors of cellular reuptakePotential disadvantagesn“Off-targets” problem (FAAH inhibitors)nRaise non-endocannabinoid substratesRaise non-endocannabinoid substratesnActivate non-cannabinoid receptors (e.g. Activate non-cannabinoid receptors (e.g. TRPV1)TRPV1)nAA-5-HT: FAAH/TRPV1 block
14、er (AA-5-HT: FAAH/TRPV1 blocker (strategystrategy) )nSome reuptake inhibitor (AM404)Some reuptake inhibitor (AM404)n“No develop” (MAGLs inhibitors)n“Time point” problem (Reuptake inhibitors)nIntroductionnUps and downs of endocannabinoids in diseasenTherapeutic use of indirect agonistsnTherapeutic us
15、e of inverse agonists/antagonistsnCB1 receptor antagonistsnCatabolism disordersCatabolism disordersnNicotine or Cocaine dependenceNicotine or Cocaine dependencenOthersOthersnCB2 receptor antagonistsnAnti-inflammatoryAnti-inflammatorynAnti-allergicAnti-allergicnAutoimmune disordersAutoimmune disorder
16、sCB1 receptor antagonists/inverse CB1 receptor antagonists/inverse agonists in agonists in clinicalclinical trials (not all) trials (not all)CB2 receptor antagonists/inverse CB2 receptor antagonists/inverse agonists in agonists in preclinicalpreclinical trials (not all) trials (not all)Potential dis
17、advantagesnNot as neutral antagonists but as inverse agonists (non-specific effects)nInterference with unconcerned disorders in which endocannabinoids might have protective effectsPerhaps no other signalling system Perhaps no other signalling system discovered during the past 15 years is raising dis
18、covered during the past 15 years is raising as many expectations for the development of as many expectations for the development of new therapeutic drugs, encompassing such a new therapeutic drugs, encompassing such a variety of pathological conditions, targeting variety of pathological conditions, targeting so many different organs and tissues, and so many different organs and tissues, and using such a wide range of potential using such a wide range of potential strategies for treatment, as the strategies for treatment, as the endocannabinoid systemendocannabinoid system. .
