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Rapid CommunicationMinireview—Axelrod Symposium 2017

Biased Agonism in Drug Discovery—Is It Too Soon to Choose a Path?

Martin C. Michel and Steven J. Charlton
Molecular Pharmacology April 2018, 93 (4) 259-265; DOI: https://doi.org/10.1124/mol.117.110890
Martin C. Michel
Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Life Sciences, University of Nottingham, Nottingham, United Kingdom (S.J.C.); and Excellerate Biosciences Ltd., MediCity, Nottingham, United Kingdom (S.J.C.)
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Steven J. Charlton
Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Life Sciences, University of Nottingham, Nottingham, United Kingdom (S.J.C.); and Excellerate Biosciences Ltd., MediCity, Nottingham, United Kingdom (S.J.C.)
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Abstract

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.

Footnotes

    • Received October 20, 2017.
    • Accepted January 1, 2018.
  • The work in the laboratory of M.C.M. has been or presently is supported by the Deutsche Forschungsgemeinschaft (Mi 294/8-1) and Velicept Therapeutics.

  • M.C.M. is a former employee of Boehringer Ingelheim. He also has received consultancy honoraria from Dr. Wilmar Schwabe and Velicept Therapeutics, and is a shareholder of the latter company. S.J.C. is a founding Director and Chief Scientific Officer of Excellerate Bioscience, and a former employee of Novartis.

  • https://doi.org/10.1124/mol.117.110890.

  • Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 93 (4)
Molecular Pharmacology
Vol. 93, Issue 4
1 Apr 2018
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Rapid CommunicationMinireview—Axelrod Symposium 2017

Biased Agonism in Drug Discovery

Martin C. Michel and Steven J. Charlton
Molecular Pharmacology April 1, 2018, 93 (4) 259-265; DOI: https://doi.org/10.1124/mol.117.110890

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Rapid CommunicationMinireview—Axelrod Symposium 2017

Biased Agonism in Drug Discovery

Martin C. Michel and Steven J. Charlton
Molecular Pharmacology April 1, 2018, 93 (4) 259-265; DOI: https://doi.org/10.1124/mol.117.110890
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