This is a competitive renewal for a project (DA-3801) aimed at understanding the molecular mechanism of action of cannabinoids. It will seek to identify the molecular properties required for cannabimimetic activity by studying experimentally the conformational properties of cannabimimetic agents and their interactions with membrane preparations and individual membrane components. During the past three years our studies have focused on the classical cannabinoids which include the naturally occurring analogs and others having closely related structures. We now propose to expand the scope of this work by including two additional groups of drugs shown to have cannabimetic activities, namely; (a) the non- classical cannabinoids synthesized by Pfizer (NCCs); and (b) some aminoalkylindole analogs (AAIs) synthesized by Sterling Research. Each group of drugs is chosen judiciously and includes analogs closely related in structure but having a wide range of potencies. The project includes detailed studies on (a) the conformational properties of the drug molecules in solution and in membrane environments using high resolution NMR methods; (b) the interactions of the drug molecules with membrane using 2H, 13C, and 31P solid state NMR and their orientations in membranes using 2H solid state NMR; (c) the topographical and geometrical features of the drug:membrane interactions using small angle x-ray and neutron diffraction; (d) the local environment of the drug in the membrane using high resolution NMR techniques for solids (MASS) and Fourier transform infrared (FTIR); (e) representation of the experimentally determined drug:membrane interactions using computer graphics. Our findings will be correlated with several biochemical effects of the cannabimimetic agents in brain synaptosomes. Direct information regarding the active site of the """"""""cannabinoid receptor"""""""" will be obtained with the help of photoaffinity labels. Future plans include studies of drug:receptor interactions using purified cannabinoid receptor preparations as these become available. Such studies will be conducted by following the above-mentioned approaches with appropriate modification when necessary. Information on the sites of cannabimetic activity in the brain will be obtained using 19F NMR in whole animals.
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