Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues

Cécile Béguin, Justin Potuzak, Wei Xu, Lee Yuan Liu-Chen, John M. Streicher, Chad E. Groer, Laura M. Bohn, William A. Carlezon, Bruce M. Cohen

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as pharmacological tools, we have modified 12-epi-salvinorin A, a compound which we have previously observed to be a KOPR partial agonist. Five analogues of 12-epi-salvinorin A were synthesized and their effects on G protein activation as well as β-arrestin2 recruitment were evaluated. Only 12-epi-salvinorin A (1) partially activated signaling through G proteins, yet acted as a full agonist in the β-arrestin 2 DiscoveRx assay. Other salvinorin analogues tested in these functional assays were full agonists in both assays of KOPR activation. By comparison, the non-selective opioid ligand nalbuphine, known to be a partial agonist for G-protein activation, was also a partial agonist for the β-arrestin mediated signaling pathway activated through KOPR.

Original languageEnglish (US)
Pages (from-to)1023-1026
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2012
Externally publishedYes

Keywords

  • Anxiety
  • Drug addiction
  • Kappa opioid receptor
  • Mood
  • Partial agonist
  • Salvinorin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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