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.