The Quantitative Characterization of Functional Allosteric Effects

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 9.22
DOI:  10.1002/cpph.18
Online Posting Date:  March, 2017
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Seven‐transmembrane receptors (7TMRs or GPCRs [G protein–coupled receptors]) are nature's prototypic allosteric proteins in that they mediate the interaction between ligand binding to the receptor and the receptor interacting with another cell signaling protein. A growing class of potential drugs acting through 7TMRs are allosteric in nature in that they bind to a separate site on the receptor protein to modify the interactions between the receptor, natural binding/orthosteric ligand, and signaling proteins. Two main allosteric compound categories are those that increase (positive allosteric modulators [PAMs]) and those that decrease (negative allosteric modulators [NAMs]) receptor‐mediated responses. Described in this overview are the molecular parameters used to measure and quantify the interaction of PAMs and NAMs with GPCRs. © 2017 by John Wiley & Sons, Inc.

Keywords: allosteric; drug activity; allosteric drugs; quantifying drug activity

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Table of Contents

  • Introduction
  • The Functional Allosteric Model
  • Case 1: Quantifying PAM EFFECTS with no Change in Agonist Maximum
  • Case 2: Quantifying PAM Effects with a Change in the Maximal Response
  • Case 3: PAM Effects—the R50 Curve as the “Workhorse” of PAM Drug Discovery
  • Case 4: PAM Agonists
  • Case 5: Surmountable Antagonism with a NAM
  • Case 6: Insurmountable Antagonism with a NAM
  • Why Quantify Allosteric Parameters?
  • Conclusions
  • Literature Cited
  • Figures
  • Tables
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Literature Cited

Literature Cited
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