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

J Pharmacol Exp Ther. 2015 Jan;352(1):98-109. doi: 10.1124/jpet.114.216820. Epub 2014 Oct 15.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • 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