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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


Jeremy Shonberg

Arthur Christopoulos

Laura Lopez

Peter J Scammells

Ben Capuano

Associate Professor


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.


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.

Journal Article Type Review
Acceptance Date May 3, 2014
Online Publication Date May 5, 2014
Publication Date 2014-11
Deposit Date Apr 22, 2020
Journal Medicinal Research Reviews
Print ISSN 0198-6325
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 34
Issue 6
Pages 1286-1330
Public URL
Publisher URL