RECEPTOR SPECIFIC ENKEPHALIN ANALOGUES

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 include: 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.