Effect of modification of the basic residues of dynorphin A-(1-13) amide on kappa opioid receptor selectivity and opioid activity

J Med Chem. 1992 Nov 13;35(23):4330-3. doi: 10.1021/jm00101a010.


A series of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) analogues containing lysine or N epsilon-acetyllysine (Lys(Ac)) was prepared by solid-phase peptide synthesis and evaluated for opioid receptor affinity in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI). Substitutions were made at positions 6, 7, 9, 11, and 13, the basic amino acids in the C-terminus of the peptide, in order to assess the individual contributions of these residues to the kappa opioid receptor affinity and selectivity of Dyn A-(1-13)NH2. While substitutions of Lys(Ac) for Arg in position 6 did not affect kappa receptor affinity, it enhanced affinity for mu and delta receptors and therefore caused a loss of kappa receptor selectivity. When Lys(Ac) was substituted for Arg9, kappa opioid receptor affinity was enhanced and kappa receptor selectivity was retained. Replacement for Arg7, Lys11, or Lys13 by Lys(Ac) resulted in both decreased affinity and selectivity for kappa receptors. These results demonstrate the importance of Arg6 to the receptor selectivity profile of Dyn A-(1-13)NH2 and indicate that, of the five basic residues in the C-terminus, only Arg9 can be replaced by a nonbasic residue without substantial loss of kappa opioid receptor selectivity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / analysis
  • Animals
  • Chromatography, High Pressure Liquid
  • Dynorphins / analogs & derivatives*
  • Guinea Pigs
  • Molecular Sequence Data
  • Muscle, Smooth / drug effects
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / metabolism
  • Structure-Activity Relationship


  • Amino Acids
  • Peptide Fragments
  • Receptors, Opioid
  • Dynorphins