The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.

Autor:	White KL; 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.)., Robinson JE; 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.)., Zhu H; 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.)., DiBerto JF; 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.)., Polepally PR; 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.)., Zjawiony JK; 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.)., Nichols DE; 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.)., Malanga CJ; 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.)., Roth BL; 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.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2015 Jan; Vol. 352 (1), pp. 98-109. Date of Electronic Publication: 2014 Oct 15.
DOI:	10.1124/jpet.114.216820
Abstrakt:	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. (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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