Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists

@article{Gillis2020LowIE,
  title={Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists},
  author={Alexander Gillis and Arisbel B. Gondin and Andrea Kliewer and Julie Sanchez and Herman D. Lim and Claudia Alamein and Preeti Manandhar and Marina Santiago and Sebastian Fritzwanker and Frank Schmiedel and Timothy A. Katte and Tristan A. Reekie and Natasha Lillia Grimsey and Michael Kassiou and Barrie Kellam and Cornelius Krasel and Michelle L. Halls and Mark Connor and Jonathan Robert Lane and Stefan Schulz and Macdonald J. Christie and Meritxell Canals},
  journal={Science Signaling},
  year={2020},
  volume={13}
}
Low intrinsic efficacy can explain the reduced side effects of apparently biased μ-opioid receptor agonists. Opioids: Efficacy versus bias Because of its antinociceptive effects, the μ-opioid receptor (MOR) is an important target for pain management, but serious side effects limit the use of drugs that target this GPCR. Because the MOR stimulates intracellular signaling through both G proteins and β-arrestins, G protein–biased agonists have been developed to promote pain relief without causing… 
Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists.
TLDR
The data in the Science Signaling paper provide strong corroborating evidence that G protein signaling bias may be a means of improving opioid analgesia while avoiding certain undesirable side effects.
Re-evaluating how low intrinsic efficacy and apparent bias for G protein activation relates to the improved side effect profiles of new opioid agonists
In a recent report by Gillis et al., 2020 (1), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory
Low intrinsic efficacy alone cannot explain the improved side effect profiles of new opioid agonists
TLDR
The data in the Science Signaling manuscript does provide strong corroborating evidence that G protein signaling bias may be a means to improve opioid analgesia while avoiding certain undesirable side effects.
Signaling diversity of mu- and delta- opioid receptor ligands: Re-evaluating the benefits of β-arrestin/G protein signaling bias.
TLDR
The signaling mechanisms underlying desired and undesired effects of opioids are reviewed and biased agonism at opioid receptors is described and how signaling kinetics and cellular background can influence the magnitude and directionality of bias at those receptors are explored.
Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors
TLDR
The state-of-the-art on addictive properties of G protein-biased μ-opioid receptor agonists are discussed as well as whether these compounds can diminish any symptoms of opioid addiction.
Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
TLDR
Overall, the current data suggests—and it supports—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics, and shows that oliceridine, PZM21 and SR–17018 behave as partial agonists.
Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor.
TLDR
The extent to which current lead compounds represent mechanistically novel, extremely G protein-biased agonists is in question, as is the underlying assumption that β-arrestin2 mediates deleterious opioid effects.
Intrinsic Efficacy of Opioid Ligands and Its Importance for Apparent Bias, Operational Analysis, and Therapeutic Window
TLDR
T theoretical and experimental evidence is provided showing that failure to consider the assumptions of the operational model can lead to large distortions and overestimation of actual bias, and low intrinsic efficacy is a major determinant of these distortions.
Strategies for Developing κ Opioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects
TLDR
A new approach is proposed to combine KOPr agonists with μ, δ, or nociceptin opioid receptor activation to obtain mixed opioid receptor agonists, therefore negating the adverse effects and retaining the therapeutic effect.
Evaluation of G protein bias and β-arrestin 2 signaling in opioid-induced respiratory depression.
TLDR
Protection from respiratory depression displayed by newly developed G-protein biased agonists is due to factors other than G- protein versus arrestin bias, and there is substantial evidence that G-proteins do, in fact, mediate respiratory depression by actions in respiratory-controlling brainstem neurons.
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References

SHOWING 1-10 OF 87 REFERENCES
A Biased View of μ-Opioid Receptors?
TLDR
Critically examining the evidence that G protein bias really is desirable and also by discussing whether the ligands so far developed are clearly biased in vitro and whether this produces responses in vivo that might be commensurate with such bias.
Biased mu‐opioid receptor ligands: a promising new generation of pain therapeutics
TLDR
A review of biased MOR ligands discovered using empirical, rational and natural product approaches with an emphasis on biased mu opioid receptor pharmacology highlights how far opioid pharmacology has evolved.
Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics
TLDR
It is found that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.
Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?
TLDR
The strategies that led to the development of biased μ-OR agonists, and potential areas for improvement, are discussed, with an emphasis on structural aspects of the ligand-receptor recognition process.
Systematic analysis of factors influencing observations of biased agonism at the mu-opioid receptor.
TLDR
This study systematically assessed the impact of differential cellular protein complement, signalling kinetics and receptor species on previous descriptions of biased agonism at MOP by several opioid peptides and synthetic opioids, and shows that all these factors need to be carefully determined and reported when consideringbiased agonism.
Efficacy and ligand bias at the μ‐opioid receptor
  • E. Kelly
  • Chemistry, Medicine
    British journal of pharmacology
  • 2013
TLDR
The basic meaning of terms including efficacy, intrinsic activity and intrinsic efficacy is discussed, along with their relevance to the field of MOP receptor pharmacology, and in particular in relation to biased agonism at this important GPCR.
Biased Signaling of the Mu Opioid Receptor Revealed in Native Neurons
TLDR
This work selected a set of clinical and novel mu agonists, and profiled their activities in transfected cell assays using advanced biosensors and in native neurons from knock-in mice expressing traceable receptors endogenously, supporting in vivo translatability of biased signaling for mu opioid drugs.
Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects
TLDR
These findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance and predict that G-protein-biased µ-agonists are still likely to elicit severe adverse effects.
Ligand bias at the μ-opioid receptor.
  • E. Kelly
  • Chemistry, Medicine
    Biochemical Society transactions
  • 2013
TLDR
Attempts to define ligand bias at any GPCR on the basis of the visual inspection of concentration-response curves or comparison of maximum response (Emax) values can be misleading, and reliable estimations of relative agonist efficacy are needed to calculate bias effectively.
A G Protein-Biased Ligand at the μ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine
TLDR
The discovery of TRV130 is reported, a novel MOR G protein-biased ligand that successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology, and may be a safer and more tolerable therapeutic for treating severe pain.
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