Design, synthesis, and evaluation of new endomorphin analogs with enhanced central antinociception after peripheral administration

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5393-7. doi: 10.1016/j.bmcl.2015.09.025. Epub 2015 Sep 11.

Abstract

We synthesized two novel endomorphin-1 (EM-1) analogs by substituting the C-terminus residue with (thienyl)-α-methylene-β-amino acids (Map). Several in vitro and in vivo assays were used to determine the activity of the analogs. The two EM-1 analogs showed subnanomolar binding affinity and functional activity at the μ-opioid receptor in HEK293 cells. Tail-flick and formalin tests further revealed that the EM-1 analogs were very effective after intravenous administration. Our results indicate that compared to endomorphin-1, the (thienyl)Map modified peptides showed improved blood-brain barrier permeability.

Keywords: Analgesia; Blood–brain barrier; Endomorphin; Unnatural amino acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Analgesics / administration & dosage
  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Blood-Brain Barrier / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Protein Binding / drug effects
  • Receptors, Opioid, mu / chemistry*
  • Receptors, Opioid, mu / metabolism

Substances

  • Analgesics
  • Oligopeptides
  • Receptors, Opioid, mu
  • endomorphin 1