|Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues.
|Year of Publication
|Béguin C, Potuzak J, Xu W, Liu-Chen L-Y, Streicher JM, Groer CE, Bohn LM, Carlezon WA, Cohen BM
|Bioorg Med Chem Lett
|2012 Jan 15
|Cell Line, Tumor, Diterpenes, Clerodane, Dose-Response Relationship, Drug, Humans, Molecular Conformation, Receptors, Opioid, kappa, Signal Transduction, Structure-Activity Relationship
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.
|Bioorg. Med. Chem. Lett.
|PubMed Central ID
|P30 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
Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues.
Faculty Member Reference:
John M. Streicher, PhD