NESS06SM, un nuovo approccio alla terapia dell'obesità

In the last decade CB1 receptor (CB1R) antagonists were among the most promising drug targets in controlling weight and energy balance. It has been reported that the hyperactivity and up-regulation of CB1R in both the peripheral (liver, visceral fat and muscle) and the central (hypothalamus, prefrontal cortex, amygdala, hippocampus, nucleus accumbens) nervous systems (CNS) are associated to metabolic disorders. The discovery of the role of this cannabinoid sub-receptor in hyperphagia and weight gain led many groups in the last two decades to focus their attention to the synthesis of compounds able to selectively block CB1R. The CB1R inverse agonist SR141716A (rimonabant), the first candidate based on this strategy, was launched on European market, although it was withdrawn by European Medicines Agency (EMA) for its adverse effects, particularly for psychiatric side effects such as induction of anxiety and depression. In particular, SR141716A side effects have been principally related to its both CB1 inverse agonism and blood brain barrier (BBB) permeability with its consequence on CNS functionality. Therefore the development of anti-obesity drugs targeting CB1R has been globally revised. However, novel strategies have been recently adopted to assure CB1R-mediated anti-obesity activity by overcoming SR141716A side effects: the development of CB1R neutral antagonists or of CB1R blockers acting selectively at peripheral level. In fact it has been ascertained that metabolic syndrome benefits can be assured not only by centrally active compounds but also by a selective modulation of peripheral CB1R. Here we have characterized the pharmacology of a new CB1R neutral antagonist compound: 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta(1,2-c)pyrazole-3-carboxamide, namely NESS06SM. We found that NESS06SM is characterized by good affinity for CB1R, absence of cellular toxicity, and 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. In fact, the mRNA gene expression in 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. In contrast to rimonabant treatment, the chronic administration of NESS06SM did not change mRNA expression of both monoaminergic transporters and neurotrophins highly related with anxiety and mood disorders. The obtained profiles suggested a possible reduction of harmful effects after treatment with novel CB1R antagonist compared to those reported for rimonabant. Our results suggested 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 rimonabant side effects. Therefore the novel CB1R neutral antagonist could represent a useful candidate agent for the treatment of obesity and its metabolic complications.