title: NESS038C6, a novel selective CB1 antagonist agent with anti-obesity activity and improved molecular profile.
abstract: The present work aims to study the effects induced by a chronic treatment with a novel CB1 antagonist (NESS038C6) in C57BL/6N diet-induced obesity (DIO) mice. Mice treated with NESS038C6 and fed with a fat diet (NESS038C6 FD) were compared with the following three reference experimental groups: DIO mice fed with the same fat diet used for NESS038C6 and treated with vehicle or the reference CB1 antagonist/inverse agonist rimonabant, "VH FD" and "SR141716 FD", respectively; DIO mice treated with vehicle and switched to a normal diet (VH ND). NESS038C6 chronic treatment (30 mg/kg/day for 31 days) determined a significant reduction in DIO mice weight relative to that of VH FD. The entity of the effect was comparable to that detected in both SR141716 FD and VH ND groups. Moreover, if compared to VH FD, NESS038C6 FD evidenced: (i) improvement of cardiovascular risk factors; (ii) significant decrease in adipose tissue leptin expression; (iii) increase in mRNA expression of hypothalamic orexigenic peptides and a decrease of anorexigenic peptides; (iv) expression increase of metabolic enzymes and peroxisome proliferator-activated receptor-α in the liver; (v) normalization of monoaminergic transporters and neurotrophic expression in mesolimbic area. However, in contrast to the case of rimonabant, the novel CB1 antagonist improved the disrupted expression profile of genes linked to the hunger-satiety circuit, without altering monoaminergic transmission. In conclusion, the novel CB1 antagonist compound NESS038C6 may represent a useful candidate agent for the treatment of obesity and its metabolic complications, without or with reduced side effects relative to those instead observed with rimonabant.
authors: CNR, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, Italy. andrea.mastinu@ift.cnr.it
authors: Andrea
authors: A
authors: Mastinu
authors: Marilena
authors: M
authors: Pira
authors: Luca
authors: L
authors: Pani
authors: Gérard Aimè
authors: GA
authors: Pinna
authors: Paolo
authors: P
authors: Lazzari
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D001786:Blood Glucose; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D050152:Intra-Abdominal Fat / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D000637:Transaminases / Q000097:blood; D014280:Triglycerides / Q000097:blood
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D063387:Cannabinoid Receptor Antagonists; D004041:Dietary Fats; D050483:Dopamine Plasma Membrane Transport Proteins; D007191:Indazoles; C577574:N-piperidinyl-7-bromo-1-(2',4'-dichlorophenyl)-4,5-dihydro-1H-thieno(2,3-g) indazol-3-carboxamide; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D013876:Thiophenes; D014280:Triglycerides; D020932:Nerve Growth Factor; D002784:Cholesterol; D000637:Transaminases; D000077285:Rimonabant