Solid state NMR studies of interactions of cannabinergic ligands with lipid membrane systems

Several major cannabinergic ligands, including Δ8-tetrahydrocannabinol (Δ8-THC), arachidonylethanolamide (anandamide), W1N55212-2, CP55940, SR141716 and their analogs have been systematically studied using different solid-state NMR techniques and differential scanning calorimetry (DSC) on their interactions with phospholipid membrane preparations. ^ Solid-state static 2H-NMR and DSC have been employed to study the perturbation effects on the lipid membrane by the cannabinoids. The results show that cannabinoids are able to modulate the local dynamics of lipid membrane characteristically; each ligand demonstrated a unique perturbation effect on different sites of lipid membrane structure. A novel concept was proposed about the interplay of cannabinoid ligand, lipid membrane and cannabinoid receptors. ^ The location, conformation and dynamics of the endogenous cannabinoid, anandamide, in the lipid membrane were elucidated using multiple-spin solid-state rotational-echo double resonance (REDOR) and static 2H NMR techniques. A novel methodology for determining the ligand conformation in lipid membrane is proposed and realized by exploiting the bilayer lattice as a three-dimensional reference grid. Novel molecular mechanism on how the endocannabinoid interact with its receptors was proposed. ^ The transport and diffusion of Δ8-THC and its O-methyl ether (Me-Δ8-THC) across lipid membrane were investigated using Paramagnetic Relaxation Enhanced (PRE) solid-state static 2H-NMR. The result shows that both compounds can be incorporated into lipid preparations in relatively high concentrations; Me-Δ8-THC is found resides in the bilayer at two distinct sites when the molar concentration is above 10%, as opposed to Δ8-THC which resides in only one preferred location near the bilayer interface. A novel model of how a lipophilic drug across biological membrane is proposed based on the study. ^ The structure and dynamic properties of lipid membrane at different phase has been (re)investigated using Cross Polarization and Magic Angle Spin (CP/MAS) 13C NMR. Discrepancy problems of lipid NMR spectra in the literature were resolved. A novel molecular mechanism of lipid membrane phase transitions was proposed based on new NMR data. The effects of Δ8-THC and Me-Δ8-THC on lipid phase and structural perturbation has been studied with CP/MAS 13C NMR and the spectra were interpreted with new mechanism.