Design, synthesis, binding, and molecular modeling studies of new potent ligands of cannabinoid receptors

In our ongoing program aimed at the design, synthesis, and biological evaluation of novel cannabinoid receptor ligands derived from olivetol and hexyl-resorcinol, we have designed a structural model for new derivatives on the basis of a previous study. Here we report the synthesis, binding, and molecular modeling studies of new potent compounds with high affinity toward CB₁ and CB₂ receptors. Compounds with amidic 'heads' with alkyloxy chains varying in length from 8 to 12 carbon atoms showed nanomolar affinity for both receptors, depending on the type of aromatic backbone. Two of the new compounds, although not very potent, exhibit selectivity for CB₁ receptors (CB₁/CB₂ = 0.07 and 0.08, respectively). Molecular modeling studies fitted this new class of cannabinoid ligands into a CB₁ receptor model, and the qualitative analysis of the results was in general agreement with the CB₁ affinity constants observed experimentally for these derivatives.