This is a request for ADAMHA RSCDA II. 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 but covering a wide range of potencies and will include detailed studies on: (a) the conformational properties of the cannabinoids in solu- tion using high resolution NMR techniques; (b) the interactions of cannabinoids and their orientations in model and biological membranes (synaptosomal plasma membranes) using (2)H,(13)C and (31)P solid state NMR techniques; (c) the topographical and geometrical features of the drug:membrane interactions using x-ray and neutron diffraction; (d) the cannabinoid local environment in the membrane using high resolution NMR techniques for solids (MASS) and Fourier transform infrared; (e) representation of the cannabinoid:membrane interactions based on information from our experimental findings using computer graphics. Our findings will be correlated with several biochemical effects of cannabinoids on by brain synaptosomes. Future plans include a) studying cannabinoid effects on other relevant membrane systems (lipid and/or protein components); b) obtaining direct evidence on the site of cannabinoid action through the use of NMR techniques (e.g. (19)F NMR in membranes, cell cultures and whole animals) and by using affinity labeling. Our studies will require extensive synthesis of specifically (2)H,(13)C and (19)F labeled cannabinoid analogs and phospholipids including a small number of novel cannabinoid analogs. Although the bulk of the studies described in this proposal deal with the effects of cannabinoids on the lipid component of the membrane, the methods described here are equally applicable for studying the effects of cannabinoids on membrane-associated proteins if such relevant proteins are identified by ourselves or by other groups during the course of our investigations. The methodologies developed for the study of cannabinoids will be applicable to other drugs of abuse e.g. opioids and cocaine. Data obtained from such studies will be useful for the design of novel therapeutic agents.
| Järbe, Torbjörn U C; Deng, Hongfen; Vadivel, Subramanian K et al. (2011) Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (?(9)-tetrahydrocannabinol) discrimination for rats. Behav Pharmacol 22:498-507 |
