We propose to develop a series of cyclic and otherwise conformationally restricted peptide analogues which have high receptor selectivity, high agonist or antagonist potency, high stability in vivo, and prolonged activity for delta and mu opioid receptors. For this purpose, our program utilizes a multidisciplinary approach combining modern synthetic amino acid and peptide chemistry, conformational analysis, dynamics, and peptide drug design, with biochemical, biophysical, physiological, and behavior pharmacology.
Our specific aims i nclude: 1) design, synthesis and evaluation of novel enkephalin analogues with delta opioid receptor agonist activity and selectivity; 2) development of delta opioid receptor antagonists with high selectivity; 3) design, synthesis and evaluation of cycli, conformationally-constrained somatostatin-like peptides with little or no somatostatin activity, but with high potency and specificity for mu opioid receptors; 4) examination in detail of the conformational and dynamic properties of the most potent and selective analogues from 1, 2, and 3 to obtain insight into the rational design of more selective or potent analogues using modern graphics and computational methods; 5) to examine in detail the binding activities of these compounds at mu and delta opioid receptors (the most selective analogues with be radiolabeled and receptor localized in the brain by modern autoradiographic methods); 6) to obtain a comprehensive evaluation of the opioid agonist and antagonist in vitro and in vivo activities of the analogues we have prepared and compare these activities with standard drugs; and 7) to use the above results to design more specific and more potent analogues for the delta and mu receptor. The long term goals of this research are to develop an understanding of the physiological roles of the various opioid receptors, and to develop ligands for these receptors which can be used for the treatment of disease.
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