Endomorphin-2 analogs containing modified tyrosines: Biological and theoretical investigation of the influence on conformation and pharmacological profile

Eur J Med Chem. 2019 Oct 1:179:527-536. doi: 10.1016/j.ejmech.2019.06.077. Epub 2019 Jun 28.

Abstract

New analogs of the endogenous opioid agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) have been obtained by introducing modified tyrosines at the position 1 of the sequence. For all analogs, the cis/trans conformation ratio about the tyramine-Pro amide bond, lipophilicity, receptor affinities, and functional activities, have been determined. Among the novel derivatives, [Dmt(3'-Cl)]1EM-2 (4) stood out for its subnanomolar μ-opioid receptor affinity and potent agonist activity, superior to that of the parent peptide EM-2. Hybrid quantum mechanics/molecular mechanics docking computations supported the cis tyramine-Pro bioactive conformation, and allowed us to analyze the contribution of the substituents of the "message" tyramine to binding, highlighting the role of halogen-bonding in the higher receptor affinity of peptide 4.

Keywords: Halogen-bond; Molecular docking; Opioid peptides; Tyrosine analogs.

MeSH terms

  • Analgesics, Opioid / chemical synthesis
  • Analgesics, Opioid / chemistry
  • Analgesics, Opioid / pharmacology*
  • Crystallography, X-Ray
  • Density Functional Theory*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Receptors, Opioid / agonists*
  • Structure-Activity Relationship
  • Tyrosine / chemistry
  • Tyrosine / pharmacology*

Substances

  • Analgesics, Opioid
  • Oligopeptides
  • Receptors, Opioid
  • endomorphin 2
  • Tyrosine