Unravelling Intrinsic Efficacy and Ligand Bias at G Protein Coupled Receptors: A Practical Guide to Assessing Functional Data

Biochem Pharmacol. 2016 Feb 1;101:1-12. doi: 10.1016/j.bcp.2015.10.011. Epub 2015 Oct 23.

Abstract

Stephenson's empirical definition of an agonist, as a ligand with binding affinity and intrinsic efficacy (the ability to activate the receptor once bound), underpins classical receptor pharmacology. Quantifying intrinsic efficacy using functional concentration response relationships has always presented an experimental challenge. The requirement for realistic determination of efficacy is emphasised by recent developments in our understanding of G protein coupled receptor (GPCR) agonists, with recognition that some ligands stabilise different active conformations of the receptor, leading to pathway-selective, or biased agonism. Biased ligands have potential as therapeutics with improved selectivity and clinical efficacy, but there are also pitfalls to the identification of pathway selective effects. Here we explore the basics of concentration response curve analysis, beginning with the need to distinguish ligand bias from other influences of the functional system under study. We consider the different approaches that have been used to quantify and compare biased ligands, many of which are based on the Black and Leff operational model of agonism. Some of the practical issues that accompany these analyses are highlighted, with opportunities to improve estimates in future, particularly in the separation of true agonist intrinsic efficacy from the contributions of system dependent coupling efficiency. Such methods are by their nature practical approaches, and all rely on Stephenson's separation of affinity and efficacy parameters, which are interdependent at the mechanistic level. Nevertheless, operational analysis methods can be justified by mechanistic models of GPCR activation, and if used wisely are key elements to biased ligand identification.

Keywords: Affinity; Agonist; Efficacy; G protein coupled receptor; Ligand bias; Operational model.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • Drug Discovery
  • Drugs, Investigational / pharmacology*
  • Humans
  • Kinetics
  • Ligands
  • Models, Molecular*
  • Protein Conformation
  • Protein Stability / drug effects
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects*

Substances

  • Drugs, Investigational
  • Ligands
  • Receptors, G-Protein-Coupled