DESIGN AND SYNTHESIS OF A BICYCLIC NONPEPTIDE BETA-BEND MIMETIC OF ENKEPHALIN

If the important functional groups of a biologically active peptide can be arrayed on a non-peptide framework in the ''biologically active conformation'' it may be possible to maximize the receptor interaction and eliminate or reduce the number of amide bonds that are available for proteolytic enzyme cleavage. Thus, we have designed and synthesized the 2,5,7-trisubstituted 2,3,4,4a,7,7a-hexahydro-pyrano[2,3-b]pyrrole ring system as the basis for non-peptide mimetic analogs for peptides that prefer the beta-bend conformation. Computer assisted molecular modeling studies have indicated that the resulting analogs closely resemble the functional group positioning particularly of type I and I' peptide beta-bends. Completed analogs of Leu-enkephalin have been synthesized and shown to be potent naloxone-reversible agonists in the electrically stimulated guinea pig ileum assay.