Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates

Trends Pharmacol Sci. 2007 Aug;28(8):374-81. doi: 10.1016/ Epub 2007 Jul 13.


Antagonist affinity measurements have traditionally been considered important in characterizing the cell-surface receptors present in a particular cell or tissue. A central assumption has been that antagonist affinity is constant for a given receptor-antagonist interaction, regardless of the agonist used to stimulate that receptor or the downstream response that is measured. As a consequence, changes in antagonist affinity values have been taken as initial evidence for the presence of novel receptor subtypes. Emerging evidence suggests, however, that receptors can possess multiple binding sites and the same receptor can show different antagonist affinity measurements under distinct experimental conditions. Here, we discuss several mechanisms by which antagonists have different affinities for the same receptor as a consequence of allosterism, coupling to different G proteins, multiple (but non-interacting) receptor sites, and signal-pathway-dependent pharmacology (where the pharmacology observed varies depending on the signalling pathway measured).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Binding, Competitive
  • Humans
  • Models, Biological
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism
  • Protein Binding
  • Protein Conformation
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / chemistry*
  • Signal Transduction*


  • Pharmaceutical Preparations
  • Receptors, G-Protein-Coupled