Small angle X-ray diffraction studies of (-)-delta 8-tetrahydrocannabinol and its O-methyl analog in membranes

Small angle X-ray diffraction was used to study the topography of (-)-delta 8-tetrahydrocannabinol (delta 8-THC) and its pharmacologically inactive methoxy analog (-)-O-methyl-delta 8-tetrahydrocannabinol (Me-delta 8-THC) in a membrane. The membrane preparations were partially hydrated dimyristoylphosphatidylcholine (DMPC) bilayers. Comparisons between electron density profiles from the drug-containing and drug-free membranes showed that the amphipathic delta 8-THC residues near the interface of the bilayer where the polar phenolic OH of the drug molecule is oriented towards the corresponding polar side of the phospholipid bilayer. Conversely, the highly hydrophobic Me-delta 8-THC distributes deeper in the bilayer away from the interface. Our results point out these two structurally-related, but pharmacologically very different, cannabinoids interact with membranes in strikingly different manners. This observation may, in part, explain the different pharmacological properties of the two cannabinoids.