Function of negative charge in the "address domain" of deltorphins

J Med Chem. 1991 Apr;34(4):1350-5. doi: 10.1021/jm00108a017.


Deltorphins A, B, and C exhibit high delta-affinities (Ki = 0.12-0.31 nM) and very high delta-receptor binding selectivities (Ki mu/Ki delta = 1800-4100). A study of the delta-receptor binding properties of 15 deltorphin analogues focused primarily on the influence of the anionic group in the C-terminal tetrapeptide. Amidation of the beta-carboxyl groups of [Asp7], [Glu4], or [Asp4] in deltorphins A, B, and C, respectively, yielded peptides with enhanced mu-receptor affinities and minor changes in delta-affinities (Ki delta = 0.20-0.65 nM), but 5-8-fold diminished delta-selectivities. A free C-terminal carboxyl group markedly reduced delta-affinities and decreased delta-selectivities 6-11-fold; thus, the C-terminal amide group critically facilitates delta-affinity. Modifications in the anionic charged group or hydrophobic residues in the C-terminal tetrapeptide address domain of deltorphin A altered spatial distributions critical for delta-affinity and selectivity; e.g., [Nle6]deltorphin A enhanced mu-affinity and lowered delta-selectivity by two-thirds; the progressive, step-wise repositioning of Asp in deltorphin C (from position 4 to 7) was accompanied by linear decreases in delta-affinities and -selectivities, and increased mu-affinities of these peptides; enhancement of the charge density to -2, in [Asp6, Asp-OH7]deltorphin A, decreased delta-affinity and -selectivity, while [Asp4,5,His7]deltorphin A bound to neither mu- nor delta-sites. These results demonstrate that while an anionic group may occasionally facilitate high delta-receptor affinity, it represents an absolute requirement for the high delta-binding selectivity of these peptides. The locations of the charged groups relative to hydrophobic residues in the address domain of the peptide are also critical determinants for both delta-affinity and -selectivity.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Cell Membrane / metabolism
  • Enkephalin, Leucine-2-Alanine / analogs & derivatives
  • Enkephalin, Leucine-2-Alanine / metabolism
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Rats
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Structure-Activity Relationship


  • Oligopeptides
  • Receptors, Opioid
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • deltorphin
  • Enkephalin, Leucine-2-Alanine
  • enkephalinamide-Leu, Ala(2)-