Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors

Trends Pharmacol Sci. 2007 Aug;28(8):407-15. doi: 10.1016/j.tips.2007.06.009. Epub 2007 Jul 13.

Abstract

Seven-transmembrane receptors are prototypic allosteric proteins with the ability to adopt numerous conformations, many of which interact with cellular partners to initiate cellular biochemical processes. Defining efficacy as the ability of ligands to stabilize some of these conformations (which, in turn, possess physiological activity) presents a wider definition of efficacy beyond simple integrated cellular response; numerous or 'pluridimensional' efficacies are required to describe ligands. Specifically, some agonists might only partially activate the library of potential signaling systems in a cell or some antagonists might actively induce receptor internalization without activation. This article reviews data to demonstrate that there is no longer support for a linear view of efficacy whereby a single receptor activation state triggers all possible receptor interactions with a cell. Instead, a view of collateral efficacy, in which ligands can produce portions of the possible behaviors of receptors, is presented. Concepts related to the molecular mechanism for this effect (discussed in the literature as 'stimulus trafficking', 'biased agonism' or 'functional selectivity') and discussion of the possible therapeutic implications of this mechanism are presented.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation
  • Drug Design*
  • Humans
  • Kinetics
  • Ligands*
  • Models, Biological
  • Protein Binding
  • Protein Conformation
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / chemistry
  • Treatment Outcome

Substances

  • Ligands
  • Receptors, G-Protein-Coupled
  • seven-transmembrane G-protein-coupled receptor