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

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Abstract
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 emodeled 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.