On resin click-chemistry-mediated synthesis of novel enkephalin analogues with potent anti-nociceptive activity

Sci Rep. 2019 Apr 8;9(1):5771. doi: 10.1038/s41598-019-42289-5.

Abstract

Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This entailed the solid-phase synthesis of two enkephalin precursor chains followed by a CuI-catalyzed azide-alkyne cycloaddition, with the aim of improving in vivo analgesic efficacy versus DPDPE. NOVA2 showed good affinity and selectivity for the μ-opioid receptor (KI of 59.2 nM, EC50 of 12.9 nM, EMax of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology
  • Animals
  • CHO Cells
  • Click Chemistry / methods*
  • Cricetinae
  • Cricetulus
  • Cycloaddition Reaction / methods
  • Enkephalin, D-Penicillamine (2,5)- / analogs & derivatives*
  • Enkephalin, D-Penicillamine (2,5)- / chemical synthesis
  • Enkephalin, D-Penicillamine (2,5)- / pharmacology
  • Humans
  • Male
  • Mice
  • Protein Binding
  • Receptors, Opioid, mu / metabolism

Substances

  • Analgesics
  • Receptors, Opioid, mu
  • Enkephalin, D-Penicillamine (2,5)-