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

Cyf N. Ramos-Colon, Yeon Sun Lee, Michael Remesic, Sara M. Hall, Justin Lavigne, Peg Davis, Alexander J. Sandweiss, Mary I. McIntosh, Jessica Hanson, Tally M. Largent-Milnes, Todd W. Vanderah, John Streicher, Frank Porreca, Victor J. Hruby

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10 Scopus citations


Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the ΰ 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.

Original languageEnglish (US)
Pages (from-to)10291-10298
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number22
StatePublished - Nov 23 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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