This proposal outlines a multidisciplinary effort by four principal investigators to continue development of a series of cyclic and linear conformationally constrained peptide analogues which have high receptor specificity high agonist or antagonist biological activities, high stability in vivo, and prolonged biological activity at kappa (kappa) opioid receptors. This multidisciplinary approach combines modern computer assisted molecular modeling, organic amino acid and peptide chemistry, conformational analysis and molecular mechanics and dynamics calculations, and biochemical, biophysical, physiological and pharmacological studies.
The specific aims of this investigation include: a) continues development in the design, synthesis, and evaluation of novel peptides and peptide mimetics derived from dynorphin and related peptides which possess high kappa opioid receptor potency and specificity; b) comprehensive examination of the potency and specificity of all new ligands for kappa vs. mu and delta opioid receptors using radioligand binding techniques. The most selective and potent ligands will be radiolabeled to high specific activity and used in extensive radioligand binding studies and for receptor localization using autoradiography; c) opioid agonist or antagonist activities will be evaluated in vitro using the GPI, MVD, LVP and HVD assays to establish receptor selectivity and potency; d) in vivo kappa receptor properties will be evaluated with the most selectivity compounds using among other assays, the mouse abdominal stretch test following intrathecal administration, and the standard mouse hot plate test; 5) careful examination of the conformational and dynamic properties of the most potent and selective analogues using 1D and 2D nuclear magnetic resonance spectroscopy, molecular mechanics calculations, and other biophysical techniques; and 6) using all of the above results of the design and synthesis of novel compounds with more potent and selective biological activities, and to test conformational models proposed for kappa receptor selective ligands. The long term goal of this research is to develop an understanding of the physiological roles of the kappa opioid receptor in comparison to other opioid receptors, and to develop ligands for the kappa receptors that can be used for the treatment of disease.
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