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Amino Acids

, Volume 7, Issue 3, pp 291–304 | Cite as

Prerequisite for His4 in deltorphin A for highδ opioid receptor selectivity

  • S. Salvadori
  • R. Guerrini
  • V. Forlani
  • S. D. Bryant
  • M. Attila
  • L. H. Lazarus
Article

Summary

Analysis of deltorphin A position 4 analogues included: backbone constrained N α MeHis, spinacine (Spi), N α MePhe and the tetrahydroisoquinoline-3-carboxylic acid (Tic); spatially confined side-chain (Phg); and imidazole alkylation ofl- andd-His4 enantiomers. Highδ selectivity was lost with the following replacements: N α MeHis4, N α MePhe4 and Phg4 reducedδ binding and the constrained residues also increasedµ binding; ring closure between the side-chain and amino group to yield Spi4 or Tic4 increasedµ affinity. Imidazole methylation of His4 marginally affected opioid binding and doubledδ selectivity; alkylatedd-His4-derivatives generally maintainedδ selectivity in spite of decreasedδ affinities. Thus, His4 imidazole preservesδ selectivity by facilitating highδ binding and by repulsion at theµ receptor. Several low energy conformers of deltorphin A indicated that the His4 imidazole preferred a spatial orientation parallel to the phenolic side-chain of Tyr1 suggestive that this conformation might contribute to highδ affinity and selectivity.

Keywords

Amino Acids Deltorphins Peptide synthesis Opioid receptors Molecular dynamics simulations 

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Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • S. Salvadori
    • 1
  • R. Guerrini
    • 1
  • V. Forlani
    • 1
  • S. D. Bryant
    • 2
  • M. Attila
    • 3
  • L. H. Lazarus
    • 2
  1. 1.Department of Pharmaceutical ScienceUniversity of FerraraFerraraItaly
  2. 2.Peptide Neurochemistry SectionLaboratory of Environmental Neuroscience, National Institute of Environmental Health SciencesResearch Triangle ParkUSA
  3. 3.Department of Pharmacology, Division of Pharmacy and ToxicologyUniversity of HelsinkiHelsinkiFinland

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