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: Kate L White, J Elliott Robinson, Hu Zhu, Jeffrey F DiBerto, Prabhakar R Polepally, Jordan K Zjawiony, David E Nichols, C J Malanga, Bryan L Roth
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 352 Issue 1 Pg. 98-109 (Jan 2015) ISSN: 1521-0103 [Electronic] United States
• PMID: 25320048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• 22-thiocyanatosalvinorin A
• ARRB2 protein, human
• Analgesics, Opioid
• Arrb2 protein, mouse
• Arrestins
• Diterpenes, Clerodane
• Ligands
• Receptors, Opioid, kappa
• beta-Arrestin 2
• beta-Arrestins
• GTP-Binding Proteins

Topics

• Analgesics, Opioid (adverse effects, pharmacology)
• Animals
• Arrestins (metabolism)
• Conditioning, Psychological (drug effects)
• Diterpenes, Clerodane (adverse effects, pharmacology)
• GTP-Binding Proteins (metabolism)
• HEK293 Cells
• Humans
• Ligands
• Mice
• Receptors, Opioid, kappa (agonists)
• Signal Transduction (drug effects)
• beta-Arrestin 2
• beta-Arrestins