Peptide models of dynorphin A(1-17) incorporating minimally homologous substitutes for the potential amphiphilic beta strand in residues 7-15

Two peptide models of dynorphin A(1-17) have been synthesized. These peptides incorporate a minimally homologous substitute sequence for residues 6-17, including alternating lysine and valine residues substituting for the potential amphiphilic beta-strand structure in positions 7-15. Model 1 retains Pro10 from the native sequence, but model 2 does not. Compression isotherms of peptide monolayers at the air-water interface and CD spectra of peptide films adsorbed from aqueous solution onto siliconized quartz slides were evaluated by comparison to those of idealized amphiphilic alpha-helical, beta-sheet, and disordered peptides. Dynorphin A(1-17) was mostly disordered, whereas beta-endorphin was alpha helical. Dynorphin model 1 had properties similar to those of dynorphin A(1-17) at these interfaces, but model 2 formed strongly amphiphilic beta sheets. In binding assays to mu-, delta-, and kappa-opioid receptors in guinea pig brain membranes, model 1 reproduced the high potency and selectivity of dynorphin A(1-17) for kappa receptors, and model 2 was only 3 times less potent and less selective for these receptors. Both peptide models retained the high, kappa-selective agonist activity of dynorphin A(1-17) in guinea pig ileum assays, and like dynorphin A(1-17), model 1 had little activity in the rat vas deferens assay. In view of the minimal homology of the modeled dynorphin structures, these studies support current models of membrane-catalyzed opioid ligand-receptor interactions and suggest a role for the amphiphilic alpha-helical and beta-strand structures in beta-endorphin and dynorphin A(1-17), respectively, in this process.