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Cited by 294

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Biased Receptor Signaling in Drug Discovery

Open access
Kenakin, Terry·2019·Pharmacological Reviews
DOI 10.1124/pr.118.016790
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Abstract

A great deal of experimental evidence suggests that ligands can stabilize different receptor active states that go on to interact with cellular signaling proteins to form a range of different complexes in varying quantities. In pleiotropically linked receptor systems, this leads to selective activation of some signaling pathways at the expense of others (biased signaling). This article summarizes the current knowledge about the complex components of receptor systems, the evidence that biased signaling is used in natural physiology to fine-tune signaling, and the current thoughts on how this mechanism may be applied to the design of better drugs. Although this is a fairly newly discovered phenomenon, theoretical and experimental data suggest that it is a ubiquitous behavior of ligands and receptors and to be expected. Biased signaling is simple to detect in vitro and there are numerous methods to quantify the effect with scales that can be used to optimize this activity in structure-activity medicinal chemistry studies. At present, the major hurdle in the application of this mechanism to therapeutics is the translation of in vitro bias to in vivo effect; this is because of the numerous factors that can modify measures of bias in natural physiologic systems. In spite of this, biased signaling still has the potential to justify revisiting of receptor targets previously thought to be intractable and also furnishes the means to pursue targets previously thought to be forbidden due to deleterious physiology (as these may be eliminated through biased signaling).

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Metadata

Authors
Kenakin, T.
Venue
Pharmacological Reviews
Publisher
Elsevier BV
Published
2019-04
Volume
71
Issue
2
Pages
267-315
ISSN
0031-6997 (ISSN-L)
DOI
10.1124/pr.118.016790
OpenAlex
W2923681300
Cited by
294
References
525
FWCI
10.96
Type
journal article
Language
en
Open access
bronze
Licence
  • www.elsevier.com/tdm/userlicense/1.0/ (tdm)
  • www.elsevier.com/legal/tdmrep-license (tdm)

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Kenakin, T. (2019). Biased Receptor Signaling in Drug Discovery. Pharmacological Reviews. https://doi.org/10.1124/pr.118.016790

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