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

Authors: Beguin C, Potuzak J, Xu W, Liu-Chen, LY, Streicher, JM, Groer, CE, Bohn, LM, Carlezon, WA, Jr., and Cohen, BM
Publisher/Year: Bioorg Med Chem Lett 22(2):1023-6.
Pub Med ID/Journal ID: PMID:22204910

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.