Behavioural Brain Research 234 (2012) 192–204 Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l ho me pa ge: www.elsevier.com/locate/bbr Research report NESS038C6, a novel selective CB1 antagonist agent with anti-obesity activity and improved molecular profile Andrea Mastinu a,b,∗ , Marilena Pira a,c , Luca Pani a,1 , Gérard Aimè Pinna c , Paolo Lazzari c,d,∗∗ a CNR, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, Italy b Dipartimento Scienze Biomediche, Università degli Studi di Cagliari, s.p. 8 Monserrato-Sestu Km. 0, 700 – 09042 – Monserrato Cagliari, Italy c Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F.Muroni 23/A, 07100 Sassari, Italy d Neuroscienze Pharmaness S.c.ar.l., Edificio 5, Loc. Piscinamanna, 09010 Pula, Italy h i g h l i g h t s ◮ NESS038C6 produced a significant weight loss in DIO mice fed with a fat diet. ◮ Chronic treatment with NESS038C6 improved cardiovascular risk factors. ◮ NESS038C6 regulated the molecular pathways between hypothalamus and fat tissue. ◮ NESS038C6 upregulated metabolic enzymes and PPAR- mRNA in the liver. ◮ Our compound upregulated monoaminergic transporters and neurotrophic factors mRNA. a r t i c l e i n f o Article history: Received 14 June 2012 Received in revised form 27 June 2012 Accepted 28 June 2012 Available online 4 July 2012 Keywords: NESS038C6 Dio mice Blood parameters Leptin pathway Monoaminergic transporters Neurotrophic factors a b s t r a c t The present work aims to study the effects induced by a chronic treatment with a novel CB1 antago- nist (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- 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. © 2012 Elsevier B.V. All rights reserved. ∗ Corresponding author at: CNR, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, Italy. Tel.: +39 0709242026; fax: +39 0709242206. ∗∗ Corresponding author at: Neuroscienze PharmaNess S.c.a.r.l., Edificio 5, Loc. Piscinamanna, 09100 Pula (CA), Italy. Tel: +39 0709242025; fax: +39 0709242206. E-mail addresses: andrea.mastinu@ift.cnr.it (A. Mastinu), paolo.lazzari@pharmaness.it (P. Lazzari). 1 Current address: Agenzia Italiana del Farmaco (AIFA), Via del Tritone 181, 00187 Roma, Italy. 1. Introduction Obesity has become a major public health concern in indus- trialized countries. Worldwide there are 1.1 billion overweight people with a BMI between 25 kg/m 2 and 30 kg/m 2 and 312 mil- lion with a BMI >30 kg/m 2 [20]. A projection for the year 2030 estimates that 366 million people will suffer from obesity [54]. In addition, abdominal obesity is significantly associated with vari- ous metabolic abnormalities, including insulin resistance, impaired glucose tolerance/type-2 diabetes, and atherogenic dyslipidaemia 0166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2012.06.033