Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1286 - 1330 |
| Number of pages | 45 |
| Journal | Medicinal Research Reviews |
| Volume | 34 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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Biased agonism at G protein-coupled receptors: The promise and the challenges - A medicinal chemistry perspective. / Shonberg, Jeremy; Lopez Munoz, Laura; Scammells, Peter John; Christopoulos, Arthur; Capuano, Benvenuto; Lane, Jonathan Robert David.
In: Medicinal Research Reviews, Vol. 34, No. 6, 2014, p. 1286 - 1330.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Biased agonism at G protein-coupled receptors: The promise and the challenges - A medicinal chemistry perspective
AU - Shonberg, Jeremy
AU - Lopez Munoz, Laura
AU - Scammells, Peter John
AU - Christopoulos, Arthur
AU - Capuano, Benvenuto
AU - Lane, Jonathan Robert David
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://onlinelibrary.wiley.com/doi/10.1002/med.21318/epdf
U2 - 10.1002/med.21318
DO - 10.1002/med.21318
M3 - Article
VL - 34
SP - 1286
EP - 1330
JO - Medicinal Research Reviews
JF - Medicinal Research Reviews
SN - 0198-6325
IS - 6
ER -