ArticleProceedings of the National Academy of Sciences of the United States of America2013
Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 75 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
75 citing papers in PubMed, 132 citations in OpenAlex.
- Mechanistic and therapeutic insights into class A GPCR dimers in neuropsychiatric disorders.npj drug discovery · 2026Review
- Divergence in μ and δ opioid receptor pharmacology in neurons and antinociceptive efficacy in neuropathic pain: Insights from MP135 and CYM51010.British journal of pharmacology · 2026Article
- GPCR Heterodimers: Implications for Biased Signaling.Handbook of experimental pharmacology · 2026Review
- Identification of small molecule ligands for GPR83 that modulate morphine antinociception and reward.Molecular pharmacology · 2026Article
- Single-molecule methods for characterizing receptor dimers reveal metastable opioid receptor homodimers that induce functional modulation.Nature communications · 2025Article
- Single-molecule characterization of opioid receptor heterodimers reveals soluble µ-δ dimer blocker peptide alleviates morphine tolerance.Nature communications · 2025Article
- The Orexin System in Addiction: Neuromodulatory Interactions and Therapeutic Potential.Brain sciences · 2025Review
- Recommended Opioid Receptor Tool Compounds: ComparativeACS pharmacology & translational science · 2025Article
- G Protein-Coupled Receptor Dimerization-What Next?International journal of molecular sciences · 2024Review
- Activation of the Mu-Delta Opioid Receptor Heteromers Blocks Morphine Rewarding Effects.The international journal of neuropsychopharmacology · 2023Article
- CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats.Pharmacological reports : PR · 2023Article
- 7-Chloroquinolinehydrazones as First-in-Class Anticancer Experimental Drugs in the NCI-60 Screen among Different Investigated Series of Aryl, Quinoline, Pyridine, Benzothiazole and Imidazolehydrazones.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Receptor Transporter Protein 4 (RTP4) in the Hypothalamus Is Involved in the Development of Antinociceptive Tolerance to Morphine.Biomolecules · 2022Article
- G protein-coupled receptor-effector macromolecular membrane assemblies (GEMMAs).Pharmacology & therapeutics · 2022Review
- Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology.Pharmacology & therapeutics · 2022Review
- Class A and C GPCR Dimers in Neurodegenerative Diseases.Current neuropharmacology · 2022Review
- GPCR heteromers: An overview of their classification, function and physiological relevance.Frontiers in endocrinology · 2022Review
- Opioid Analgesia and Opioid-Induced Adverse Effects: A Review.Pharmaceuticals (Basel, Switzerland) · 2021Review
- In Vitro Analyses of Spinach-Derived Opioid Peptides, Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and β-Arrestin-Mediated Pathways.Molecules (Basel, Switzerland) · 2021Article
- Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors.Pharmacological reports : PR · 2021Review
15 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issuedSaldanha, Adrian S [corrected to Saldanha, S Adrian]; Eberhart, Christina [added]
Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
G protein-coupled receptors play a pivotal role in many physiological signaling pathways. Mounting evidence suggests that G protein-coupled receptors, including opioid receptors, form dimers, and dimerization is necessary for receptor maturation, signaling, and trafficking. However, the physiological role of dimerization in vivo has not been well-explored because of the lack of tools to study these dimers in endogenous systems. To address this problem, we previously generated antibodies to μ-δ opioid receptor (μOR-δOR) dimers and used them to study the pharmacology and signaling by this heteromer. We also showed that the heteromer exhibits restricted distribution in the brain and that its abundance is increased in response to chronic morphine administration. Thus, the μOR-δOR heteromer represents a potentially unique target for the development of therapeutics to treat pain. Here, we report the identification of compounds targeting μOR-δOR heteromers through high-throughput screening of a small-molecule library. These compounds exhibit activity in μOR-δOR cells but not μOR or δOR cells alone. Among them, CYM51010 was found to be a μOR-δOR-biased ligand, because its activity is blocked by the μOR-δOR heteromer antibody. Notably, systemic administration of CYM51010 induced antinociceptive activity similar to morphine, and chronic administration of CYM51010 resulted in lesser antinociceptive tolerance compared with morphine. Taken together, these results suggest that CYM51010, a μOR-δOR-biased ligand, could serve as a scaffold for the development of a unique type (heteromer-biased) of drug that is more potent and without the severe side effects associated with conventional clinical opioids.
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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.