Herkinorin analogues with differential beta-arrestin-2 interactions.
Salvinorin A is a psychoactive natural product that has been found to be a potent and selective kappa opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent kappa opioid receptor signaling yet leads to less receptor downregulation than observed with other kappa agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin ( 1c), with high affinity at the microOR. We recently reported that 1c does not promote the recruitment of beta-arrestin-2 to the microOR or receptor internalization. Here we describe three new derivatives of 1c ( 3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of beta-arrestin-2 to the microOR and receptor internalization. When the important role micro opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, micro opioids derived from salvinorin A may offer a unique template for the development of functionally selective mu opioid receptor-ligands with the ability to produce analgesia while limiting adverse side effects.
Tidgewell
Kevin
K
Division of Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, Iowa 52242, USA.
Groer
Chad E
CE
Harding
Wayne W
WW
Lozama
Anthony
A
Schmidt
Matthew
M
Marquam
Alfred
A
Hiemstra
Jessica
J
Partilla
John S
JS
Dersch
Christina M
CM
Rothman
Richard B
RB
Bohn
Laura M
LM
Prisinzano
Thomas E
TE
D019390:Arrestins / Q000737:chemistry*; D002460:Cell Line; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; D019390:Arrestins; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C090499:salvinorin A