The long term goal of this research project is to elucidate the basis for the actions of Cannaboids (CBs) at the molecular level. To this end, we are developing the elements of an understanding of the relationships between cannabinoid ligand structure: cannabinoid receptor activation at an atomic level of detail. The research plan is organized around two emphases: ligand-ligand studies and ligand-receptor studies. In ligand studies, we will infer information about the CB receptors and/or modes of binding interactions at these receptors from a correlation between experimentally determined receptor affinities and biological activities and structural and electronic features of a series of cannabinoid ligands. These include endogenous cannabinoid analogs designed to test the hypothesis that the endogenous cannabinoids bind to the CB1 receptor in extended conformations, as well as analogs of the CB1 antagonist, SR141716A and the CB2 antagonist, SR144528, each designed to test specific hypothesized receptor interactions. At each step, our work will be aided and supplemented by collaboration with medicinal chemists and pharmacologists. Compounds proposed for synthesis here have been specific hypotheses which have emerged during the current grant period. Pharmacological results from evaluation of these new compounds will be used to refine the pharmacophores we construct in our ligand-ligand studies. In ligand-receptor studies, we will analyze the interaction of CB ligands with 3D models of the cannabinoid CB1 and CB2 receptors which we have developed and refined. These studies will focus not only on required recognition elements but also on the consequences of ligand binding. For example, studies of the interaction of SR141716A, SR144528 and their analogs in the Hx 3-4-5-6 region of the CB receptors will be conducted to test the hypothesis that interaction with W6.48 results in the reported antagonism/inverse agonism produced by these compounds at the CB receptors. This work will be aided and supplemented at each step by collaboration with experimental molecular biologists. Many of the compounds proposed for synthesis in this application will be used in combination with mutation studies to test the involvement of specific amino acids with specific ligand functional groups. Results of mutation studies will be used to refine our receptor models, such that at any given time, these models reflect the current state of knowledge in the cannabinoid field.
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