Synthesis and analgesic activity of alkylated, reduced and constrained oligoheterocyclic peptidomimetic analogs of Leu-enkephalin

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4482-4485. doi: 10.1016/j.bmcl.2014.07.090. Epub 2014 Aug 8.

Abstract

We report the design and the parallel solid phase synthesis of linear and oligoheterocyclic peptidomimetic analogs of Leu-enkephalin. The described peptidomimetics represent different unique scaffolds that distribute in the space the peptidyl side chains of amino acids essential for biological activity and mimic the bioactive conformation of the Leu-enkephalin peptide. All the compounds were screened in competitive radioligand binding assays to determine their affinities for μ-(MOR), and κ-(KOR) opioid receptors. A reduced analog of Leu-enkephalin TPI1879-26 with activity Ki=60 nM for the mu receptor was identified.

Keywords: Combinatorial chemistry; Oligoheterocyclic peptidomimetics; Opioid receptors; Peptidomimetics; Solid-phase synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Dose-Response Relationship, Drug
  • Enkephalin, Leucine / analogs & derivatives*
  • Enkephalin, Leucine / chemistry
  • Enkephalin, Leucine / pharmacology*
  • Heterocyclic Compounds / chemistry*
  • Humans
  • Molecular Structure
  • Oxidation-Reduction
  • Peptidomimetics / chemistry*
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Heterocyclic Compounds
  • Peptidomimetics
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Enkephalin, Leucine