Structure-activity relationship studies of functionally selective kappa opioid receptor agonists that modulate ERK 1/2 phosphorylation while preserving G protein over βarrestin2 signaling bias

ACS Chem Neurosci. 2015 Aug 19;6(8):1411-9. doi: 10.1021/acschemneuro.5b00092. Epub 2015 May 1.


Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure-activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling.

Keywords: Functional selectivity; G protein coupling; GPCR; MAP kinase; arrestin; biased agonism.

Publication types

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

MeSH terms

  • Analgesics, Opioid / chemistry*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Arrestins / metabolism
  • Benzeneacetamides / pharmacology
  • CHO Cells
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • GTP-Binding Proteins / metabolism
  • Humans
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation / drug effects
  • Pyrrolidines / pharmacology
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, kappa / metabolism
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • beta-Arrestins


  • Analgesics, Opioid
  • Arrestins
  • Benzeneacetamides
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Recombinant Proteins
  • beta-Arrestins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • GTP-Binding Proteins
  • U 69593