Arizona Health Sciences

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

TitleDifferential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues.
Publication TypeJournal Article
Year of Publication2012
AuthorsBéguin C, Potuzak J, Xu W, Liu-Chen L-Y, Streicher JM, Groer CE, Bohn LM, Carlezon WA, Cohen BM
JournalBioorg Med Chem Lett
Volume22
Issue2
Pagination1023-6
Date Published2012 Jan 15
ISSN1464-3405
KeywordsCell Line, Tumor, Diterpenes, Clerodane, Dose-Response Relationship, Drug, Humans, Molecular Conformation, Receptors, Opioid, kappa, Signal Transduction, Structure-Activity Relationship
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.

DOI10.1016/j.bmcl.2011.11.128
Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID22204910
PubMed Central IDPMC3926198
Grant ListP30 DA013429 / DA / NIDA NIH HHS / United States
R01 DA017302 / DA / NIDA NIH HHS / United States
R01 DA031927 / DA / NIDA NIH HHS / United States
DA 17302 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
John M. Streicher, PhD