Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues.
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.
Mailman Research Center, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA. cbeguin@mclean.harvard.edu
Cécile
C
Béguin
Justin
J
Potuzak
Wei
W
Xu
Lee-Yuan
LY
Liu-Chen
John M
JM
Streicher
Chad E
CE
Groer
Laura M
LM
Bohn
William A
WA
Carlezon
Bruce M
BM
Cohen
D045744:Cell Line, Tumor; D045785:Diterpenes, Clerodane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008968:Molecular Conformation; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; C090499:salvinorin A