Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the κ Opioid Receptor

J Med Chem. 2016 Nov 23;59(22):10291-10298. doi: 10.1021/acs.jmedchem.6b01411. Epub 2016 Nov 8.


Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the κ opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Dynorphins / chemical synthesis
  • Dynorphins / chemistry*
  • Dynorphins / pharmacology*
  • Guinea Pigs
  • Male
  • Mice
  • Mice, Inbred ICR
  • Narcotic Antagonists / chemical synthesis
  • Narcotic Antagonists / chemistry*
  • Narcotic Antagonists / pharmacology*
  • Pain / drug therapy
  • Rats
  • Receptors, Opioid, kappa / agonists*
  • Structure-Activity Relationship


  • Narcotic Antagonists
  • Receptors, Opioid, kappa
  • Dynorphins