• Cécile Béguin, Justin Potuzak, Wei Xu, Lee-Yuan Liu-Chen, John M Streicher, Chad E Groer, Laura M Bohn, William A Carlezon, and Bruce M Cohen.
• Mailman Research Center, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA. cbeguin@mclean.harvard.edu
• Bioorg. Med. Chem. Lett. 2012 Jan 15; 22 (2): 1023-6.

AbstractThe 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.Copyright © 2011 Elsevier Ltd. All rights reserved.

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