OPIOID RECEPTOR SPECIFIC PEPTIDES

We propose to develop a series of cyclic and otherwise conformationally
restricted peptide analogues which have high receptor specificity, high
agonist or antagonist biological activities, high stability in vivo, and
prolonged in vitro activity for mu and kappa opioid receptors. For this
purpose, we have developed a multidisciplinary approach combining modern
synthetic organic amino acid and peptide chemistry, conformational analysis
and peptide drug design, with biochemical, biophysical, physiological, and
behavioral pharmacology. Using this approach we will develop structure-
and conformation-biological activity relationships and insights which will
lead to compounds with specific agonist and antagonist activities at mu and
kappa opioid receptors. Specific aims include: a) continued development
of cyclic, conformationally constrained peptides (derived from
somatostatin) with high mu opioid receptor specificity and potency and
opioid antagonist activity; b) design, synthesis, and evaluation of novel
peptides derived from dynorphin and Alpha-neoendorphin with high kappa
opioid receptor potency and specificity; c) careful evaluation of the
conformational and dynamic properties of selected analogues to determine
the biophysical basis for their biological activity and to aid in the
development of a rational approach to more specific and/or potent
compounds; d) to evaluate the peptides we design and synthesize for
specific binding to mu, delta, kappa, and sigma opioid receptors in the
brain; to localize the binding sites in the brain for highly selective
radiolabeled analogues; e) to comprehensively evaluate activities in vitro
using the guinea pig ileum, mouse vas deferens, rabbit vas deferens,
hamster vas deferens, and other assays to establish receptor specificity
and to aid in the development of new, more potent and selective analogues;
f) to carefully evaluate mu and kappa activities of new compounds in vivo
using the rat urinary bladder model (mu receptor) and the mouse abdominal
stretch (kappa receptor) test after IT administration; and g) to examine
mu, delta, and kappa receptor specific analogues for activity at the
PCP/sigma receptor system in the brain using the radioligand (3H)TCP;
structure-function analysis of the natural endogenous PCP/sigma polypeptide
(once its structure has been determined) will be examined. The long term
goal of this research is 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.