STUDIES ON THE THERMOTROPIC EFFECTS OF CANNABINOIDS ON PHOSPHATIDYLCHOLINE BILAYERS USING DIFFERENTIAL SCANNING CALORIMETRY AND SMALL-ANGLEX-RAY-DIFFRACTION

We have studied the thermotropic properties of a wide variety of canna binoids in DPPC bilayers. The molecules under study were divided into four classes: (a) classical cannabinoids possessing a phenolic hydroxy l group; (b) Delta(9)-THC metabolites with an additional hydroxyl grou p on the C ring; (c) non-classical cannabinoids, and (d) cannabinoids with a protected phenolic hydroxyl group. The results showed that the first three groups have similar effects on the thermotropic properties of DPPC bilayers up to x = 0.05 (molar ratio) and that these effects do not parallel their biological activity. For concentrations less tha n x = 0.01, cannabinoids affect mainly the pretransition temperature i n a progressive manner until its final abolishment. At x = 0.05, they further affect the main phase transition by lowering its phase transit ion temperature and broadening its half width. At high concentrations the thermograms have multiple components, indicating that membranes ar e no longer homogeneous but rather consist of different domains. At th ese concentrations cannabinoids with more hydroxyl groups give simpler thermograms. Low concentrations of cannabinoids in group d affect sig nificantly the pretransition temperature, while high concentrations af fect only marginally the main phase transition by slightly lowering it s temperature and broadening its half width. These results point out t he importance of the phenolic hydroxyl group in inducing membrane pert urbations. The d-spacing data from our small angle X-ray diffraction e xperiments show that Delta(8)-THC produces significant structural chan ges in the lipid bilayer, including the gel-phase tilting angle, the i ntermolecular cooperativity and the gauche:trans conformer ratio. Conv ersely, the inactive analog Me-Delta(8)-THC does not cause drastic cha nges to the bilayer structure.