Measurement of Receptor Signaling Bias

Terry Kenakin1

1 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 2.15
DOI:  10.1002/cpph.11
Online Posting Date:  September, 2016
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G protein–coupled receptors (GPCRs) are often pleiotropically linked to numerous cellular signaling mechanisms in cells, and it is now known that many agonists differentially activate some signaling pathways at the expense of others. The mechanism for this effect is the stabilization of different active receptor states by different agonists, and it leads to varying qualities of efficacy for different agonists. Agonist bias is a powerful mechanism to amplify beneficial signals and diminish harmful signals, and thus improve the overall profile of agonist ligands. This unit describes a method to quantify agonist bias with a scale that enables medicinal chemists to amplify or reduce these effects in new molecules. The method is based on the Black/Leff operational model and yields a statistical estimate of the confidence for bias measurements. © 2016 by John Wiley & Sons, Inc.

Keywords: receptor agonists; efficacy; drug discovery; receptor signaling

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Table of Contents

  • Introduction
  • Basic Protocol 1: Comparing Agonism within a Defined Signaling Pathway
  • Support Protocol 1: Quantifying Effects of Receptor Mutation on Signaling Bias
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Literature Cited

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