ACETALINS - OPIOID RECEPTOR ANTAGONISTS DETERMINED THROUGH THE USE OFSYNTHETIC PEPTIDE COMBINATORIAL LIBRARIES

A synthetic peptide combinatorial library made up of 52,128,400 hexape ptides, each having an acetyl group at the N terminus and an amide gro up on the C terminus, was screened to find compounds able to displace tritiated [D-Ala2,MePhe4,Gly-ol5]enkephalin from mu opioid receptor bi nding sites in crude rat brain homogenates. Individual peptides with m u receptor affinity were found using an iterative process for successi vely determining the most active peptide mixtures. Upon completion of this iterative process, the three peptides with the highest affinity w ere Ac-RFMWMT-NH2, Ac-RFMWMR-NH2, and Ac-RFMWMK-NH2. These peptides sh owed high affinity for mu and kappa3 opioid receptors, somewhat lower affinity for delta receptors, weak affinity for kappa1 receptors, and no affinity for K2 receptors. They were found to be potent mu receptor antagonists in the guinea pig ileum assay and relatively weak antagon ists in the mouse vas deferens assay. These peptides represent a class of opioid receptor ligands that we have termed acetalins (acetyl plus enkephalin).