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Research ArticleNeuropharmacology

The G Protein–Biased κ-Opioid Receptor Agonist RB-64 Is Analgesic with a Unique Spectrum of Activities In Vivo

Kate L. White, J. Elliott Robinson, Hu Zhu, Jeffrey F. DiBerto, Prabhakar R. Polepally, Jordan K. Zjawiony, David E. Nichols, C. J. Malanga and Bryan L. Roth
Journal of Pharmacology and Experimental Therapeutics January 2015, 352 (1) 98-109; DOI: https://doi.org/10.1124/jpet.114.216820
Kate L. White
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.)
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J. Elliott Robinson
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.)
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Hu Zhu
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.)
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Jeffrey F. DiBerto
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.)
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Prabhakar R. Polepally
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.)
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Jordan K. Zjawiony
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.)
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David E. Nichols
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.)
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C. J. Malanga
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.)
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Bryan L. Roth
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.)
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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.

Footnotes

    • Received May 19, 2014.
    • Accepted October 10, 2014.
  • This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA017204 and P01-DA035764]; and the National Institutes of Health National Institute of Mental Health Psychoactive Drug Screening Program.

  • A preliminary account of this work was previously presented at the following meeting: White KL, Vardy E, and Roth BL (2013) Utilizing functionally selective ligands to probe specific signaling pathways of the kappa opioid receptor. 2013 Kappa Therapeutics Meeting; 2013 Apr 24–27; Cambridge, MA.

  • dx.doi.org/10.1124/jpet.114.216820.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 1
1 Jan 2015
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Research ArticleNeuropharmacology

RB-64: A G Protein–Biased KOR Agonist

Kate L. White, J. Elliott Robinson, Hu Zhu, Jeffrey F. DiBerto, Prabhakar R. Polepally, Jordan K. Zjawiony, David E. Nichols, C. J. Malanga and Bryan L. Roth
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 98-109; DOI: https://doi.org/10.1124/jpet.114.216820

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Research ArticleNeuropharmacology

RB-64: A G Protein–Biased KOR Agonist

Kate L. White, J. Elliott Robinson, Hu Zhu, Jeffrey F. DiBerto, Prabhakar R. Polepally, Jordan K. Zjawiony, David E. Nichols, C. J. Malanga and Bryan L. Roth
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 98-109; DOI: https://doi.org/10.1124/jpet.114.216820
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