Constraining Endomorphin-1 by β,α-Hybrid Dipeptide/Heterocycle Scaffolds: Identification of a Novel κ-Opioid Receptor Selective Partial Agonist

J Med Chem. 2018 Jul 12;61(13):5751-5757. doi: 10.1021/acs.jmedchem.8b00296. Epub 2018 Jul 2.

Abstract

Herein we present the expedient synthesis of endomorphin-1 analogues containing stereoisomeric β2-homo-Freidinger lactam-like scaffolds ([Amo2]EM), and we discuss opioid receptor (OR) affinity, enzymatic stability, functional activity, in vivo antinociceptive effects, and conformational and molecular docking analysis. Hence, H-Tyr-Amo-Trp-PheNH2 resulted to be a new chemotype of highly stable, selective, partial KOR agonist inducing analgesia, therefore displaying great potential interest as a painkiller possibly with reduced harmful side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / chemistry*
  • Analgesics / metabolism
  • Analgesics / pharmacology*
  • Animals
  • Dipeptides / chemistry*
  • Heterocyclic Compounds / chemistry*
  • Mice
  • Molecular Docking Simulation
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry*
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Protein Conformation
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, kappa / chemistry
  • Receptors, Opioid, kappa / metabolism

Substances

  • Analgesics
  • Dipeptides
  • Heterocyclic Compounds
  • Oligopeptides
  • Receptors, Opioid, kappa
  • endomorphin 1