A G Protein-Biased Ligand at the μ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine
Abstract
The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less β-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.
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New biased μ-opioid receptor ligands activate the G protein pathway exclusively, leading to analgesia with reduced gastrointestinal dysfunction.
“New biased µ-opioid receptor ligands activate the G protein pathway exclusively, leading to analgesia with reduced gastrointestinal dysfunction”
From Irritable bowel syndrome (2020) · cites this paper as [146]
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- Authors
- DeWire, S. M., Yamashita, D. S., Rominger, D. H., Liu, G., Cowan, C. L., Graczyk, T. M., Chen, X.-T., Pitis, P. M., Gotchev, D., Yuan, C., Koblish, M., Lark, M. W., & Violin, J. D.
- Affiliations
- Trevena, Inc. (United States) (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 344
- Issue
- 3
- Pages
- 708-717
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2165671231
- Cited by
- 647
- References
- 3
- Citations by year
- 2026: 50 · 2025: 47 · 2024: 51 · 2023: 38 · 2022: 39 · 2021: 74 · 2020: 64 · 2019: 73 · 2018: 49 · 2017: 48 · 2016: 36 · 2015: 32 · 2014: 27 · 2013: 19
- FWCI
- 17.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- TRV130, mu-opioid receptor, ligand bias, morphine, analgesia, gastrointestinal dysfunction, respiratory depression, β-arrestin2, receptor internalization, opioid side effects, severe pain
- MeSH terms
- beta-Arrestins, beta-Arrestin 2, Analgesics, Animals, Cell Line, Gastrointestinal Diseases, Humans, Ligands, Male, Mice, Inbred C57BL, Morphine, Respiratory System, Respiratory Tract Diseases, Signal Transduction, Rats, Sprague-Dawley, Receptors, Opioid, mu, Mice, Knockout, GTP-Binding Proteins, Arrestins, Gastrointestinal Tract, Receptors, G-Protein-Coupled, Mice, Rats, HEK293 Cells
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