enann相abinoidsystem内源性大麻素系统.pptVIP

Targeting the endocannabinoid system: to enhance or reduce? Vincenzo DM NATURE REVIEWS | DRUG DISCOVERY, 2008 Introduction Ups and downs of endocannabinoids in disease Therapeutic use of indirect agonists Therapeutic use of inverse agonists/antagonists Cannabinoid Endocannabinoid Anandamide 2-AG Recptors Cannabinoid receptors CB1 and CB2 Anandamide has highest affinity 2-AG has highest efficacy Retrograde signalling Other “receptors” of cannabinoid TRPV1 GPR55 ??? PPARs-alpha/beta ??? Development strategy of endocannabinoid system targeted drug Direct agonist × Tetrahydrocannabinol and its synthetic analogues Newer drugs √ Inhibiter of endocannabinoid degradation SA-47 URB597 Cannabinoid receptor (CB) antagonists Rimonabant Taranabant Introduction Ups and downs of endocannabinoids in disease Therapeutic use of indirect agonists Therapeutic use of inverse agonists/antagonists NOTE Measurement Amounts of endocannabinoid × Changes of endocannabinoid level √ Bidirectional or paradox effects Positive and negative Protective and worsening Multiple functional outcome Eatting disorders Physiological condition Adaptive response Intake of food Cope with the lack of food Pathological condition Disrupted orexigenic mechanism Neural-disease Neurodegeneration Parlinson’s disease Beta-amyloid-cytotoxicity (AD) Multiple sclerosis and experimental allergic encephalitis Amyotrophic lateral sclerosis Anxiety and depression Pain and inflammation Liver disease and osteoporosis Detrimental and beneficial effects of CB1 and CB2 respectively Hepatic pathology Chronic upregulation of endocannabinoid level Osteoporosis Other diseases Cancer Gastrointestinal inflammation Introduction Ups and downs of endocannabinoids in disease Therapeutic use of indirect agonists Therapeutic use of inverse agonists/antagonists Inhibitors of catabolism Inhibitors of catabolism FAAH blockers – more selective towards anandamide MAGLs blockers – specific for 2-AG URB-597 (prec