ArticlePLoS computational biology2020
Molecular mechanisms of fentanyl mediated β-arrestin biased signaling.
Article in PLoS computational biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
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The trial behind it
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Who cites it
29 citing papers in PubMed, 55 citations in OpenAlex.
- Structural basis of opioid receptor activation by PCP and ketamine.Nature structural & molecular biology · 2026Article
- Structure-Bias Relationship of μ-Opioid Receptor Agonists.Handbook of experimental pharmacology · 2026Review
- Opioid Analgesics: Rise and Fall of Ligand Biased Signaling and Future Perspectives in the Quest for the Holy Grail.CNS drugs · 2025Review
- Ligand-Induced Biased Activation of GPCRs: Recent Advances and New Directions from In Silico Approaches.Molecules (Basel, Switzerland) · 2025Review
- Ligand Reorganization for End-Point Binding Free Energy Calculations: Identifying Preferred Poses of Fentanyls in the μ Opioid Receptor.Journal of chemical theory and computation · 2025Article
- Impact of Intracellular Proteins on μ-Opioid Receptor Structure and Ligand Binding.The journal of physical chemistry. B · 2025Article
- Intracellular pocket conformations determine signaling efficacy through thebioRxiv : the preprint server for biology · 2024Article
- Review
- Molecular Pharmacology Profiling of Phenylfentanil and Its Analogues to Understand the Putative Involvement of an Adrenergic Mechanism in Fentanyl-Induced Respiratory Depression.Journal of medicinal chemistry · 2024Article
- Carfentanil is a β-arrestin-biased agonist at the μ opioid receptor.British journal of pharmacology · 2023Article
- Distinct Profiles of Desensitization of µ-Opioid Receptors Caused by Remifentanil or Fentanyl: In Vitro Assay with Cells and Three-Dimensional Structural Analyses.International journal of molecular sciences · 2023Article
- Binding preference at the μ-opioid receptor underlies distinct pharmacology of cyclopropyl versus valeryl analogs of fentanyl.Neuropharmacology · 2023Article
- Comparative Study of Elabela and Apelin on Apelin Receptor Activation Through β-Arrestin Recruitment.Molecular biotechnology · 2023Article
- Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse.Neuroscience bulletin · 2022Review
- Molecular Basis of Inhibitory Mechanism of Naltrexone and Its Metabolites through Structural and Energetic Analyses.Molecules (Basel, Switzerland) · 2022Article
- Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Recent Molecular Insights into Agonist-specific Binding to the Mu-Opioid Receptor.Frontiers in molecular biosciences · 2022Review
- Tyrosine 7.43 is important for mu-opioid receptor downstream signaling pathways activated by fentanyl.Frontiers in pharmacology · 2022Article
- A comprehensive evaluation of the potential binding poses of fentanyl and its analogs at the µ-opioid receptor.Computational and structural biotechnology journal · 2022Article
- Mechanisms Underlying Mu Opioid Receptor Effects on Parallel Fiber-Purkinje Cell Synaptic Transmission in Mouse Cerebellar Cortex.Frontiers in synaptic neuroscience · 2022Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or β-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent β-arrestin biased agonist, binds the μ-opioid receptor (μOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. Following an in-silico derived hypothesis we found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce β-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate an activation mechanism where the n-aniline ring of fentanyl mediates μOR β-arrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated β-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.