• 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.
• 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.).
• J. Pharmacol. Exp. Ther. 2015 Jan 1; 352 (1): 98-109.

AbstractThe 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.

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