title: NESS06SM reduces body weight with an improved profile relative to SR141716A.
abstract: We have recently synthesized a new series of 4,5-dihydrobenzo-oxa-cycloheptapyrazole derivatives with the aim to discover novel CB1 antagonist agents characterized by anti-obesity activity comparable to that of SR141716A but with reduced adverse effects such as anxiety and depression. Within the novel class, the CB1 antagonist 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta(1,2-c)pyrazole-3-carboxamide (NESS06SM) has been selected as lead compound. We found that NESS06SM is a CB1 neutral antagonist, characterized by poor blood-brain barrier permeability. Moreover, NESS06SM chronic treatment determined both anti-obesity effect and cardiovascular risk factor improvement in C57BL/6N Diet Induced Obesity (DIO) mice fed with fat diet (FD mice). In fact, the mRNA gene expression in Central Nervous System (CNS) and peripheral tissues by real time PCR, showed a significant increase of orexigenic peptides and a decrease of anorexigenic peptides elicited by NESS06SM treatment, compared to control mice fed with the same diet. Moreover, in contrast to SR141716A treatment, the chronic administration of NESS06SM did not change mRNA expression of both monoaminergic transporters and neurotrophins highly related with anxiety and mood disorders. Our results suggest that NESS06SM reduces body weight and it can restore the disrupted expression profile of genes linked to the hunger-satiety circuit without altering monoaminergic transmission probably avoiding SR141716A side effects. Therefore the novel CB1 neutral antagonist could represent a useful candidate agent for the treatment of obesity and its metabolic complications.
authors.affiliation: CNR, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy. andrea.mastinu@ift.cnr.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Mastinu
authors.forename: Marilena
authors.initials: M
authors.lastname: Pira
authors.forename: Gérard Aimè
authors.initials: GA
authors.lastname: Pinna
authors.forename: Carla
authors.initials: C
authors.lastname: Pisu
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Casu
authors.forename: Roberta
authors.initials: R
authors.lastname: Reali
authors.forename: Stefania
authors.initials: S
authors.lastname: Marcello
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001584:Benzoxepins / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D059305:Diet, High-Fat; D064429:Fatty Acid Synthases / Q000235:genetics; D005941:Glucokinase / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011770:Pyruvate Kinase / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D000077285:Rimonabant; D027981:Symporters / Q000235:genetics
chemical_list: C586703:8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta(1,2-c)pyrazole-3-carboxamide; D019440:Anti-Obesity Agents; D001584:Benzoxepins; D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D027981:Symporters; D064429:Fatty Acid Synthases; D005941:Glucokinase; D011770:Pyruvate Kinase; D000077285:Rimonabant
keywords: DIO mice; Mood disorders; NESS06SM; Obesity; SR141716A