Molecular study of endo and phytocannabinoids on lipid membranes of different composition

The discovery of the endocannabinoid system (ECS) dates back only 30 years. Although many research groups have been elucidating its components, location, functions and metabolism, the peculiarities of the compounds considered "neurotransmitters" of ECS generate questions that have not yet been answered or controversies in the literature. In this context, we studied the molecular behaviour of the main endocannabinoid compounds and the main phytocannabinoids in eukaryotic outer and inner model membranes. The high lipophilicity of these compounds gives place to the hypothesis that cannabinoids may reach the molecular targets through the lipid bilayer. This consideration is not only for the cannabinoid receptors but also for other (many) targets that these bioactive molecules modulate (Watkins, 2019; Nelson et al., 2020; Jakowiecki and Filipek, 2016). Given the reported multitarget action of these compounds and the differential behaviour towards the different receptors, studying the properties and dynamics of these cannabinoids in POPC and POPE model membranes become relevant. In this regard, we have studied the differential modulation of the endocannabinoids anandamide and 2-arachidonoyl-glycerol and the phytocannabinoids cannabidiol and trans-Δ9-tetrahydrocannabinol to eukaryotic outer and inner model membranes. Results show that behaviours favour the mobility of the bioactive molecules studied by the external eukaryotic model membrane. As well as, the internal eukaryotic model membrane is less fluid, favouring the stabilisation of folded conformations or the positioning of the molecules in the centre of the bilayer. These results provide relevant evidence that contributes to a deep inside understanding of the behaviour of the primary endogenous ligands of ECS, together with the principal phytocannabinoids of C. sativa. [Display omitted] •Endo and phytocannabinoids present differential interaction with lipid membranes.•Cannabinoids increase the disorder of hydrocarbon chains of POPC lipid membranes.•Model membrane of POPE stabilizes folded conformers of anandamide.•2-Arachidonoyl-glycerol shows a low tendency to penetrate POPC lipid membranes.•CBD and THC present differential behaviour both in POPC and POPE lipid membrane.