The objectives of the proposed research are the elucidation of the conformational and structural features required for interaction of opioid ligands at distinct opioid receptor subtypes and the utilization of this information in the design of new opioid agonists and antagonists. The approach to be followed will combine extensive conformational analysis by H-1 and C-13 NMR, circular dichroism, laser Raman spectroscopy, fluorescence energy transfer, and x-ray crystallography with the design and synthesis of carefully chosen conformationally restricted analogs of known highly receptor selective opioid peptides which themselves possess limited conformational flexibility. Correlation of conformational and structural features of related analogs with pharmacological activity will allow the identification of the precise requirements for interaction with individual classes of opioid receptors. The resulting models of opioid ligand-receptor binding (and/or transduction) will be used for the design of further analogs to test these models with the ultimate aim being the development of compounds with increased selectivity and enhanced agonist or antagonist potency. Concomitant with the studies proposed here will be the continuation of ongoing collaborations aimed at evaluating the physiological role(s) of distinct opioid receptor subtypes. These latter studies will provide essential insight to guide the direction of this proposal toward compounds with potential clinical use.
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