Delineating biased ligand efficacy at 7TM receptors from an experimental perspective

During the last 10 years, the concept of “biased agonism” also called “functional selectivity” swamped the pharmacology of 7 transmembrane receptors and paved the way for developing signaling pathway-selective drugs with increased efficacy and less adverse effects. Initially thought to select the ac...

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Bibliographic Details
Published in:The international journal of biochemistry & cell biology 2016-08, Vol.77 (Pt B), p.251-263
Main Authors: Galandrin, Ségolène, Onfroy, Lauriane, Poirot, Mathias Charles, Sénard, Jean-Michel, Galés, Céline
Format: Article
Language:English
Subjects:
Animals
Bias factor
Biological Assay - methods
Functional selectivity
G protein coupled receptor
Humans
II messengers
Ligands
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Resonance energy transfert
Signal Transduction
β-arrestin
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Summary:During the last 10 years, the concept of “biased agonism” also called “functional selectivity” swamped the pharmacology of 7 transmembrane receptors and paved the way for developing signaling pathway-selective drugs with increased efficacy and less adverse effects. Initially thought to select the activation of only a subset of the signaling pathways by the reference agonist, bias ligands revealed higher complexity as they have been shown to stabilize variable receptor conformations that associate with distinct signaling events from the reference. Today, one major challenge relies on the in vitro determination of the bias and classification of these ligands, as a prerequisite for future in vivo and clinical translation. In this review, current experimental considerations for the bias evaluation related to choice of the cellular model, of the signaling pathway as well as of the assays are presented and discussed.
ISSN:1357-2725
1878-5875
DOI:10.1016/j.biocel.2016.04.009