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 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.
Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université Toulouse, F-31432 Toulouse, France.
Ségolène
S
Galandrin
Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université Toulouse, F-31432 Toulouse, France.
Lauriane
L
Onfroy
Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université Toulouse, F-31432 Toulouse, France.
Mathias Charles
MC
Poirot
Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université Toulouse, F-31432 Toulouse, France; Service de Pharmacologie Clinique, Faculté de médecine, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse, F-31000 Toulouse, France.
Jean-Michel
JM
Sénard
Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université Toulouse, F-31432 Toulouse, France. Electronic address: celine.gales@inserm.fr.
Céline
C
Galés
D000818:Animals; D001681:Biological Assay / Q000379:methods*; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction
D008024:Ligands; D043562:Receptors, G-Protein-Coupled
Bias factor; Functional selectivity; G protein coupled receptor; II messengers; Resonance energy transfert; β-arrestin