Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands.

In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)--piperidin-1-yl-4,5-dihydrobenzo-1-6-oxa-cyclohepta[1,2-]pyrazole-3-carboxamide and its deaza cyclohexyl analogue has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of ,, derivatives -, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, and resulted in the most potent CB receptor ligands (KCB = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB antagonist activity for the majority of the new compounds, excluding compound , which showed a CB partial agonist behaviour. CB antagonist activity of was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.