The role of kinetic context in apparent biased agonism at GPCRs

Nat Commun. 2016 Feb 24;7:10842. doi: 10.1038/ncomms10842.


Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that 'kinetic context', as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aripiprazole / pharmacokinetics
  • CHO Cells
  • Cricetulus
  • Dopamine / pharmacokinetics
  • Dopamine Agonists / pharmacokinetics*
  • Indoles / pharmacokinetics
  • Kinetics
  • Ligands
  • Piperazines / pharmacokinetics
  • Piperidines / pharmacokinetics
  • Principal Component Analysis
  • Protein Stability
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / metabolism


  • Dopamine Agonists
  • Indoles
  • Ligands
  • Piperazines
  • Piperidines
  • Receptors, Dopamine D2
  • ropinirole
  • Aripiprazole
  • preclamol
  • cariprazine
  • Dopamine