Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists

The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha,gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pK(i)=7.2) as well as very potent antagonistic activity (pA(2)=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.