ArticleBritish journal of pharmacology2016
Biased ligand quantification in drug discovery: from theory to high throughput screening to identify new biased μ opioid receptor agonists.
Article in British journal of pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 61 citations in OpenAlex.
- Pharmacological stratification of public bioactivity databases: a reusable, OECD-anchored curation and benchmarking framework demonstrated for opioid receptors.Digital discovery · 2026Article
- Discovery of Biased Dual-Agonists of Glucagon-Like Peptide 1 and Glucagon Receptors through Mutation of a Conserved Aspartate.ACS medicinal chemistry letters · 2026Article
- Biased Agonism at β-Adrenoceptor Subtypes: A Drug Development Perspective.Handbook of experimental pharmacology · 2026Review
- Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor.Molecular pharmacology · 2025Article
- Biased Signaling and Its Role in the Genesis of Short- and Long-Acting βBiochemistry · 2025Article
- Biased agonism in psychopharmacology: an opportunity to improve efficacy and safety of treatments.CNS spectrums · 2025Review
- Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Effects of Biased Analogues of the Kappa Opioid Receptor Agonist, U50,488, in Preclinical Models of Pain and Side Effects.Molecules (Basel, Switzerland) · 2025Article
- Unique pharmacological properties of etrasimod among S1P receptor modulators.FEBS open bio · 2025Article
- Systematic Assessment of Human CCR7 Signalling Using NanoBRET Biosensors Points towards the Importance of the Cellular Context.Biosensors · 2024Article
- Article
- GMolecular pharmacology · 2023Article
- Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans.Molecules (Basel, Switzerland) · 2023Article
- Fingerprinting heterocellular β-adrenoceptor functional expression in the brain using agonist activity profiles.Frontiers in molecular biosciences · 2023Article
- Agonist-Dependent Coupling of the Promiscuous Adenosine AACS pharmacology & translational science · 2022Article
- Delineating the Ligand-Receptor Interactions That Lead to Biased Signaling at the μ-Opioid Receptor.Journal of chemical information and modeling · 2021Article
- Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors.RSC medicinal chemistry · 2021Review
- Discovery of μ,δ-Opioid Receptor Dual-Biased Agonists That Overcome the Limitation of Prior Biased Agonists.ACS pharmacology & translational science · 2021Article
- Respiratory depression and analgesia by opioid drugs in freely behaving larval zebrafish.eLife · 2021Article
- Construction of a Virtual Opioid Bioprofile: A Data-Driven QSAR Modeling Study to Identify New Analgesic Opioids.ACS sustainable chemistry & engineering · 2021Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeBiased GPCR ligands are able to engage with their target receptor in a manner that preferentially activates distinct downstream signalling and offers potential for next generation therapeutics. However, accurate quantification of ligand bias in vitro is complex, and current best practice is not amenable for testing large numbers of compound. We have therefore sought to apply ligand bias theory to an industrial scale screening campaign for the identification of new biased μ receptor agonists. EXPERIMENTAL APPROACH: μ receptor assays with appropriate dynamic range were developed for both Gαi -dependent signalling and β-arrestin2 recruitment. Δlog(Emax /EC50 ) analysis was validated as an alternative for the operational model of agonism in calculating pathway bias towards Gαi -dependent signalling. The analysis was applied to a high throughput screen to characterize the prevalence and nature of pathway bias among a diverse set of compounds with μ receptor agonist activity. KEY
resultsA high throughput screening campaign yielded 440 hits with greater than 10-fold bias relative to DAMGO. To validate these results, we quantified pathway bias of a subset of hits using the operational model of agonism. The high degree of correlation across these biased hits confirmed that Δlog(Emax /EC50 ) was a suitable method for identifying genuine biased ligands within a large collection of diverse compounds. CONCLUSIONS AND IMPLICATIONS: This work demonstrates that using Δlog(Emax /EC50 ), drug discovery can apply the concept of biased ligand quantification on a large scale and accelerate the deliberate discovery of novel therapeutics acting via this complex pharmacology.
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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.