Effects of chronic administration of the novel CB1 receptor ligand, E—6776, in a rat model of dietary-induced obesity

Angels Fisas1, Xavier Codony1, José Miguel Vela1, Helen Jackson2, Sharon Cheetham2, David Heal2, Helmut Buschmann1. 1Laboratorios Dr. Esteve, S.A., Barcelona, Spain, 2Pharmacology, Renasci Consultancy Ltd., Nottingham, United Kingdom.

There is a substantial body of evidence that the endocannabinoid system plays an important role in the regulation of food intake and energy balance (Kirkham, 2005). Exogenous and endogenous cannabinoid agonists produce increases in food intake and weight gain in several species, including man (Vickers et al., 2005). These effects are thought to be mediated by activation of CB1 cannabinoid receptors. Repeated administration of CB1 receptor antagonists such as rimonabant (Acomplia; SR-141716) reduce food intake and body weight in lean, genetically obese and diet-induced obesity animals (Vickers et al., 2003).

This study investigated the effects on food intake, body weight and body composition of chronic administration with the novel CB1 receptor antagonist, E-6776, ((RS)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide), in dietary-induced obese rats, a preclinical model of human obesity (Dickinson et al., 1998).

Individually-housed, mature female Wistar rats (275-325g, n= 17),, were maintained on reverse-phase lighting and allowed free access to a simplified cafeteria diet, i.e. high-fat diet, chocolate and peanuts, for 14 weeks to induce obesity and throughout the course of the experiment. Body weight and food intake were monitored during the 7 day run-in period, and daily for the 28 days of treatment (Fisas et al., 2006).

E—6776 (10 mg kg-1 po, n= 7), produced a marked, significant (p<0.001, Dunnett’s test), decrease in body weight (13%, cf controls, on Day—29). The weight-loss produced by E-6776 occurred mainly during the first week, but some gradual additional loss was also observed during the remaining treatment period. The weight-loss produced by the E-6776 was due to a significant (p<0.001, Dunnett’s test) and specific loss of body fat (80.4% to the total carcass weight difference), with no significant effect on protein, water or ash content. Consistent with many other centrally—acting anti-obesity drugs, E-6776 significantly (p<0.001, Dunnett’s test), reduced the averaged daily food intake for the first week of treatment with consumption gradually returning to the intake level of the controls thereafter.

Together, these results demonstrate the therapeutic potential of E—6776, a novel anti-obesity CB1 antagonist, in the treatment of obesity.

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