Herkinorin analogues with differential β-arrestin-2 interactions

Kevin Tidgewell, Chad K. Groer, Wayne W. Harding, Anthony Lozama, Matthew Schmidt, Alfred Marquam, Jessica Hiemstra, John S. Partilla, Christina M. Dersch, Richard B. Rothman, Laura M. Bonn, Thomas E. Prisinzano

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57 Scopus citations


Salvinorin A is a psychoactive natural product that has been found to be a potent and selective κ opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent κ opioid receptor signaling yet leads to less receptor downregulation than observed with other κ agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin (1c), with high affinity at the μOR. We recently reported that 1c does not promote the recruitment of β-arrestin-2 to the μOR or receptor internalization. Here we describe three new derivatives of 1c (3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of β-arrestin-2 to the μOR and receptor internalization. When the important role μ opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, μ opioids derived from salvinorin A may offer a unique template for the development of functionally selective μ opioid receptor-ligands with the ability to produce analgesia while limiting adverse side effects.

Original languageEnglish
Pages (from-to)2421-2431
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number8
StatePublished - Apr 24 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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