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)-<i>N</i>-piperidin-1-yl-4,5-dihydrobenzo-1<i>H</i>-6-oxa-cyclohepta[1,2-<i>c</i>]pyrazole-3-carboxamide <b>1a</b> and its deaza <i>N-</i>cyclohexyl analogue <b>1b</b> 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 <b>1a</b>,<b>b</b>, derivatives <b>1c</b>&#8722;<b>j</b>, 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, <b>1d</b> and <b>1e</b> resulted in the most potent CB₁ receptor ligands (K<i>_i</i>CB₁ = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB₁ antagonist activity for the majority of the new compounds, excluding compound <b>1e</b>, which showed a CB₁ partial agonist behaviour. CB₁ antagonist activity of <b>1b</b> was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB₁ antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.

Abstract licence: CC BY

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