The proposed study is directed towards understanding the molecular mechanism of action of cannabinoids. It will seek to identify, within the cannabinoid structures, those molecular features required to produce the membrane perturbations that result in alterations of the cellular functions. The project will focus on a carefully selected group of cannabinoid analogs closely related in structure covering a wide range of potencies and will include detailed studies on: (a) the conformational properties of the cannabinoids in solution using high resolution NMR techniques; (b) the interactions of cannabinoids with representative phospholipid model membrane using 2H, 13C and 31P solid state NMR techniques; (c) the orientation of the cannabinoids in the model membranes, using 2H solid-state NMR; the topographical and geometrical features of the drug:membrane interactions using x-ray and neutron diffraction; the cannabinoid local environment in the membrane using high resolution NMR techniques for solids (MASS) and Fourier transform infrared; representation of the cannabinoid:membrane interactions based on information from our experimental findings using computer graphics. Studies analogous to (b) and (c) will be carried out with a biological membrane preparation (synaptosomal plasma membrane). Our findings wil be correlated with the effects of cannabinoids on the uptake of biogenic amines (norepinephine, dopamine, serotonin) by brain synaptosomes. Our studies will require extensive synthesis of specifically 2H- and 13C labeled cannabinoid analogs and phospholipids including a small number of novel cannabinoid analogs.
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