The primary, long-term goals of the proposed research are: 1. The determination of the precise structural and conformational features required for ligand recognition at, mu, delta, and kappa opioid receptors. 2. The elucidation of those features which impart selectivity at individual opioid receptors, either through additional ligand-receptor interactions at the favored receptor or by impeding binding to the disfavored receptors. 3. The identification of those features that distinguish agonists from antagonists. and 4. The use of the information so gained for the design of high affinity agonists and antagonists selective for each of the three opioid receptors. The studies proposed here extend the approach used to develop a delta opioid receptor pharmacophore model to mu and kappa selective peptide leads developed in the current grant period as well as to peptidomimetic structures which represent possible leads to mu, delta, and kappa selective analogs. Prominent in the approach is the use of new methods for calculating structural models of the transmembrane domain of delta, mu, and kappa receptors (and G-protein coupled receptors, in general) to assist in the design of new opioid ligands and to complement experimental (NMR spectroscopy and x-ray diffraction) and theoretical (molecular mechanics calculations) conformational analysis of the ligands themselves. In addition to investigations directed toward the opioid receptors and their ligands, the design and synthesis of novel ligands for the opioid-related orphanin receptor (ORLI) will be pursued based upon analysis of combinatorial libraries and modeling of the orphanin receptor transmembrane domain. These studies will be done in collaboration with Richard Houghten of Torrey Pines Institute for Molecular Studies.
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