This is a competitive renewal request for a project seeking to identify the molecular features involved in cannabimimetic activity through the design and synthesis of novel compounds. In the current funding period on this project, the initial goals of the project were to focus on the requirements for activity at the cannabinoid receptor within two classes of compounds, the classical and the non-classical cannabinoids. These goals have been expanded, however, in order to take advantage of three developments in the field: first, the identification of a cannabinoid receptor subtype, CB2; second, the identification of a putative cannabinoid receptor ligand, anandamide; third, the characterization of an amidase enzyme that inactivates anandamides. The expanded scope of the project now includes the design and synthesis of anandamide analogs and the addition of the CB2 and the amidase enzyme sites as targets for structure-activity correlations. Our drug design encompasses two approaches: (a) the synthesis of novel conformationally restricted classical and non-classical cannabinoids to elaborate the first generation analogs from the current funding period, focusing on the side-chain and southern aliphatic hydroxyl pharmacophores; (b) the synthesis of novel anandamides in which the highly flexible arachidonyl fragment is conformationally restricted (this group also includes some ligands that can be considered as hybrids between the classical or non-classical cannabinoids and anandamide). The stereoelectronic properties of the novel cannabinoids will be studied, both in solution and in the membrane using high resolution NMR as well as theoretically using molecular mechanics and molecular dynamics calculations. All analogs will be tested for their affinities and functional properties on CB1 and CB2 receptors in membrane and tissue preparations, as well as in whole animals. The nature of the ligand-receptor interactions will also be explored on 3D computer models of the receptors. The anandamide analogs will also be tested for their effectiveness as anandamide amidase substrates. The data will be integrated to give detailed information on the molecular properties of the new compounds. The long-term therapeutic targets of the proposal include the development of non-opioid analgesics that are also devoid of psychotropic and immunosuppressive properties of cannabinoids; immunoregulatory agents devoid of the central effects of cannabinoids; and specific CB1 and/or CB2 receptor antagonists. It is hoped that the project will result in the development of new therapeutic analogs or will provide useful information for the design of such drug analogs.
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