ArticleProceedings of the National Academy of Sciences of the United States of America2014
Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 68 citations in OpenAlex.
- Structure-guided allosteric modulation of the delta opioid receptor.Nature communications · 2026Article
- Molecular mechanism of allosteric modulation of opioid receptors.Signal transduction and targeted therapy · 2026Article
- Effects of the Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 On Opioid Efficacy in Rat Neuropathic Pain States.bioRxiv : the preprint server for biology · 2026Article
- A mu-opioid receptor positive allosteric modulator provides opioid-sparing antinociception without enhancing opioid side effects.The Journal of pharmacology and experimental therapeutics · 2026Article
- Structure-based design of an opioid receptor modulator for enhanced morphine analgesia.Science advances · 2026Article
- Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor.Molecular pharmacology · 2025Article
- Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 Confers Agonist-Dependent G Protein Subtype Signaling Bias.Biochemistry · 2025Article
- Advances in the structural understanding of opioid allostery.Trends in pharmacological sciences · 2025Review
- Application of Mixed-Solvent Molecular Dynamics Simulations for Prediction of Allosteric Sites on G Protein-Coupled Receptors.Molecular pharmacology · 2023Article
- Three-Dimensional Structural Insights Have Revealed the Distinct Binding Interactions of Agonists, Partial Agonists, and Antagonists with the µ Opioid Receptor.International journal of molecular sciences · 2023Review
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- Molecular Basis of Inhibitory Mechanism of Naltrexone and Its Metabolites through Structural and Energetic Analyses.Molecules (Basel, Switzerland) · 2022Article
- Functional Characterization of Sodium Channel Inhibitors at the Delta-Opioid Receptor.ACS omega · 2022Article
- In Search of Synergistic Insect Repellents: Modeling of Muscarinic GPCR Interactions with Classical and Bitopic Photoactive Ligands.Molecules (Basel, Switzerland) · 2022Article
- Article
- Oxycodone in the Opioid Epidemic: High 'Liking', 'Wanting', and Abuse Liability.Cellular and molecular neurobiology · 2021Review
- Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Sodium Fluctuations in Astroglia and Their Potential Impact on Astrocyte Function.Frontiers in physiology · 2020Review
- G protein-coupled receptors of class A harness the energy of membrane potential to increase their sensitivity and selectivity.Biochimica et biophysica acta. Biomembranes · 2019Article
- Harnessing Ion-Binding Sites for GPCR Pharmacology.Pharmacological reviews · 2019Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Positive allosteric modulation of the mu-opioid receptor (MOPr), the site of action of all clinically used opioids, represents a potential approach for the management of pain. We recently reported on positive allosteric modulators of MOPr (mu-PAMs), a class A G protein coupled receptor (GPCR). This study was designed to examine the mechanism of allostery by comparing the degree to which opioid ligand structure governs modulation. To do this we examined the interaction of the mu-PAM, BMS-986122, with a chemically diverse range of MOPr orthosteric ligands. Generally, for full agonists BMS-986122 enhanced the binding affinity and potency to activate G protein with no alteration in the maximal effect. In contrast, lower efficacy agonists including morphine were insensitive to alterations in binding affinity and showed little to no change in potency to stimulate G protein. Instead, there was an increase in maximal G protein stimulation. Antagonists were unresponsive to the modulatory effects of BMS-986122. Sodium is a known endogenous allosteric modulator of MOPr and alters orthosteric agonist affinity and efficacy. The sensitivity of an orthosteric ligand to BMS-986122 was strongly correlated with its sensitivity to NaCl. In addition, BMS-986122 decreased the ability of NaCl to modulate agonist binding in an allosteric fashion. Overall, BMS-986122 displayed marked probe dependence that was based upon the efficacy of the orthosteric ligand and can be explained using the Monod-Wyman-Changeux two-state model of allostery. Furthermore, disruption of the Na(+) ion binding site may represent a common mechanism for allosteric modulation of class A GPCRs.
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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.