title: The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.
abstract: The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists.
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: Kate L
authors.initials: KL
authors.lastname: White
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: J Elliott
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: Hu
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: DiBerto
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: Prabhakar R
authors.initials: PR
authors.lastname: Polepally
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
authors.forename: C J
authors.initials: CJ
authors.lastname: Malanga
authors.affiliation: Department of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.) bryan_roth@med.unc.edu.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D045785:Diterpenes, Clerodane / Q000009:adverse effects* / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C573301:22-thiocyanatosalvinorin A; C000605254:ARRB2 protein, human; D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D045785:Diterpenes, Clerodane; D008024:Ligands; D017473:Receptors, Opioid, kappa; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019204:GTP-Binding Proteins