title: Herkinorin analogues with differential beta-arrestin-2 interactions.
abstract: 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.
authors.affiliation: Division of Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tidgewell
authors.forename: Chad E
authors.initials: CE
authors.lastname: Groer
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Harding
authors.forename: Anthony
authors.initials: A
authors.lastname: Lozama
authors.forename: Matthew
authors.initials: M
authors.lastname: Schmidt
authors.forename: Alfred
authors.initials: A
authors.lastname: Marquam
authors.forename: Jessica
authors.initials: J
authors.lastname: Hiemstra
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
mesh_terms: 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
chemical_list: 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