NESS06SM reduces body weight with an improved profile relative to SR141716A.

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.

Contrasting effects of diazepam and repeated restraint stress on latent inhibition in mice.

The effects on latent inhibition (LI; a delay in conditioning when a CS has been pre-exposed without consequences) of repeated restraint stress and the anxiolytic drug diazepam were examined in C57BL/6 mice to know whether previous aversive events or anxiolysis are factors determining the expression of LI. The LI model was optimized for this strain particularly sensitive to stress (using both the CER and the conditioned freezing procedures) and characterized with typical (haloperidol) and atypical (clozapine and olanzapine) antipsychotic drugs administered either during the conditioning or the pre-exposure phases. An acute challenge with amphetamine, a dopamine releaser, was done to verify the enhancement of hyperactivity in C57BL/6 mice after the restraint stress sensitization. At all doses tested, diazepam decreased latent inhibition when administered during the pre-exposure phase (similarly to atypical antipsychotic drugs). Repeated restraint stress enhanced LI by blocking the CS-induced freezing in pre-exposed mice. In contrast, pre-treatment with diazepam before pre-exposure allowed the expression of CS-induced freezing in stressed mice pre-exposed to the tone. It is suggested that stress and anxiolytic drugs can have opposite effects on attention or perseveration processes during learning of conflicting contingency responses.