We propose to develop a series of cyclic and other conformationally restricted analogues of enkephalin which have high receptor specificity, high agonist or antagonist biological activity, prolonged in vivo activity, and oral activity. For this purpose we outline a multidisciplinary approach combining modern conformational analysis and synthetic organic peptide chemistry with biochemical, biophysical, physiological, and behavioral pharmacology. Using this approach we will develop structure-activity relationships and conformational insights which will lead to compounds with specific agonist and antagonist activities at enkephalin receptors. These conformationally restricted analogues will be investigataed for their in vitro and in vivo biological activities and their specific binding to a variety of receptors. These biological studies will include comprehensive examination of in vitro biological responses in mouse vas deferens, guinea pig ileum, and guinea pig ileum longitudinal muscle-myenteric plexes preparation, and in vivo studies including the rat hot plate, rat tail flick, mouse writhing test and a battery of tests for examining perception of noxious and non-noxious sensory stimuli in rats, mice and guinea pigs. Binding assays will include standard opiate receptor binding assays in the rat brain. New binding assays will be developed for the membrane receptors for enkephalin in the mouse vas deferens. The results from these biological studies and careful conformational analysis will be used to design and develop more potent and specific analogues for treatment of disease.
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