Skip to main content

Research Repository

Advanced Search

Biased Agonism at G Protein‐Coupled Receptors: The Promise and the Challenges—A Medicinal Chemistry Perspective

Shonberg, Jeremy; Christopoulos, Arthur; Lopez, Laura; Scammells, Peter J; Capuano, Ben; Lane, J Robert

Authors

Jeremy Shonberg

Arthur Christopoulos

Laura Lopez

Peter J Scammells

Ben Capuano

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor



Abstract

Historically, determination of G protein‐coupled receptor (GPCR) ligand efficacy has often been restricted to identifying the ligand as an agonist or antagonist at a given signaling pathway. This classification was deemed sufficient to predict compound efficacy at all signaling endpoints, including the therapeutically relevant one(s). However, it is now apparent that ligands acting at the same GPCR can stabilize multiple, distinct, receptor conformations linked to different functional outcomes. This phenomenon, known as biased agonism, stimulus bias, or functional selectivity offers the opportunity to separate on‐target therapeutic effects from side effects through the design of drugs that show pathway selectivity. However, the medicinal chemist faces numerous challenges to develop biased ligands, including the detection and quantification of biased agonism. This review summarizes the current state of the field of research into biased agonism at GPCRs, with a particular focus on efforts to relate biased agonism to ligand structure.

Journal Article Type Review
Publication Date 2014-11
Journal Medicinal Research Reviews
Print ISSN 0198-6325
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 34
Issue 6
Pages 1286-1330
APA6 Citation Shonberg, J., Christopoulos, A., Lopez, L., Scammells, P. J., Capuano, B., & Lane, J. R. (2014). Biased Agonism at G Protein‐Coupled Receptors: The Promise and the Challenges—A Medicinal Chemistry Perspective. Medicinal Research Reviews, 34(6), 1286-1330. https://doi.org/10.1002/med.21318
DOI https://doi.org/10.1002/med.21318
Publisher URL https://onlinelibrary.wiley.com/doi/abs/10.1002/med.21318
;