Biased agonism in drug discovery: is it too soon to choose a path?
A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists stabilize receptor conformations preferentially stimulating one of these pathways, and therefore allow a more targeted modulation of cell function and treatment of...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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American Society for Pharmacology and Experimental Therapeutics
2018
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| Online Access: | https://eprints.nottingham.ac.uk/50607/ |
| _version_ | 1848798295156064256 |
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| author | Michel, Martin C. Charlton, Steven J. |
| author_facet | Michel, Martin C. Charlton, Steven J. |
| author_sort | Michel, Martin C. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists stabilize receptor conformations preferentially stimulating one of these pathways, and therefore allow a more targeted modulation of cell function and treatment of disease. Dedicated development of biased agonists has led to promising drug candidates in clinical development, such as the G protein-biased µ opioid receptor agonist oliceridine. However, leveraging the theoretical potential of biased agonism for drug discovery faces several challenges. Some of these challenges are technical, such as techniques for quantitative analysis of bias and development of suitable screening assays; others are more fundamental, such as the need to robustly identify in a very early phase which cell type harbors the cellular target of the drug candidate, which signaling pathway leads to the desired therapeutic effect, and how these pathways may be modulated in the disease to be treated. We conclude that biased agonism has potential mainly in the treatment of conditions with a well-understood pathophysiology; in contrast, it may increase effort and commercial risk under circumstances where the pathophysiology has been less well defined, as is the case with many highly innovative treatments. |
| first_indexed | 2025-11-14T20:17:30Z |
| format | Article |
| id | nottingham-50607 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:17:30Z |
| publishDate | 2018 |
| publisher | American Society for Pharmacology and Experimental Therapeutics |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-506072019-03-20T04:30:19Z https://eprints.nottingham.ac.uk/50607/ Biased agonism in drug discovery: is it too soon to choose a path? Michel, Martin C. Charlton, Steven J. A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists stabilize receptor conformations preferentially stimulating one of these pathways, and therefore allow a more targeted modulation of cell function and treatment of disease. Dedicated development of biased agonists has led to promising drug candidates in clinical development, such as the G protein-biased µ opioid receptor agonist oliceridine. However, leveraging the theoretical potential of biased agonism for drug discovery faces several challenges. Some of these challenges are technical, such as techniques for quantitative analysis of bias and development of suitable screening assays; others are more fundamental, such as the need to robustly identify in a very early phase which cell type harbors the cellular target of the drug candidate, which signaling pathway leads to the desired therapeutic effect, and how these pathways may be modulated in the disease to be treated. We conclude that biased agonism has potential mainly in the treatment of conditions with a well-understood pathophysiology; in contrast, it may increase effort and commercial risk under circumstances where the pathophysiology has been less well defined, as is the case with many highly innovative treatments. American Society for Pharmacology and Experimental Therapeutics 2018-04-01 Article PeerReviewed application/pdf en https://eprints.nottingham.ac.uk/50607/1/biased%20MP.pdf Michel, Martin C. and Charlton, Steven J. (2018) Biased agonism in drug discovery: is it too soon to choose a path? Molecular Pharmacology, 93 (4). pp. 259-265. ISSN 0026-895X https://doi.org/10.1124/mol.117.110890 doi:10.1124/mol.117.110890 doi:10.1124/mol.117.110890 |
| spellingShingle | Michel, Martin C. Charlton, Steven J. Biased agonism in drug discovery: is it too soon to choose a path? |
| title | Biased agonism in drug discovery: is it too soon to choose a path? |
| title_full | Biased agonism in drug discovery: is it too soon to choose a path? |
| title_fullStr | Biased agonism in drug discovery: is it too soon to choose a path? |
| title_full_unstemmed | Biased agonism in drug discovery: is it too soon to choose a path? |
| title_short | Biased agonism in drug discovery: is it too soon to choose a path? |
| title_sort | biased agonism in drug discovery: is it too soon to choose a path? |
| url | https://eprints.nottingham.ac.uk/50607/ https://eprints.nottingham.ac.uk/50607/ https://eprints.nottingham.ac.uk/50607/ |