How lipophilic cannabinergic ligands reach their receptor sites.

It is postulated that lipophilic ligands reach their sites of action on membrane-bound functional proteins through fast lateral diffusion across the membrane bilayer. We have shown using NMR experiments that such ligands when incorporated in a membrane system assume a preferred orientation and conformation. While occupying a specific location within the bilayer, these molecules undergo fast lateral diffusion which allows them to engage in productive interactions with their respective protein sites of action. The proposed model is discussed using a group of classical and non-classical cannabinoids as well as the endogenous cannabinoid ligand anandamide.