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Research ArticleNeuropharmacology

A G Protein-Biased Ligand at the μ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine

Scott M. DeWire, Dennis S. Yamashita, David H. Rominger, Guodong Liu, Conrad L. Cowan, Thomas M. Graczyk, Xiao-Tao Chen, Philip M. Pitis, Dimitar Gotchev, Catherine Yuan, Michael Koblish, Michael W. Lark and Jonathan D. Violin
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 708-717; DOI: https://doi.org/10.1124/jpet.112.201616
Scott M. DeWire
Trevena Inc, King of Prussia, Pennsylvania
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Dennis S. Yamashita
Trevena Inc, King of Prussia, Pennsylvania
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David H. Rominger
Trevena Inc, King of Prussia, Pennsylvania
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Guodong Liu
Trevena Inc, King of Prussia, Pennsylvania
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Conrad L. Cowan
Trevena Inc, King of Prussia, Pennsylvania
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Thomas M. Graczyk
Trevena Inc, King of Prussia, Pennsylvania
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Xiao-Tao Chen
Trevena Inc, King of Prussia, Pennsylvania
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Philip M. Pitis
Trevena Inc, King of Prussia, Pennsylvania
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Dimitar Gotchev
Trevena Inc, King of Prussia, Pennsylvania
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Catherine Yuan
Trevena Inc, King of Prussia, Pennsylvania
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Michael Koblish
Trevena Inc, King of Prussia, Pennsylvania
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Michael W. Lark
Trevena Inc, King of Prussia, Pennsylvania
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Jonathan D. Violin
Trevena Inc, King of Prussia, Pennsylvania
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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.

Footnotes

  • All work was funded by Trevena Inc. All authors are present or former employees of Trevena Inc., a privately held drug discovery company.

  • dx.doi.org/10.1124/jpet.112.201616.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Received November 5, 2012.
  • Accepted January 7, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleNeuropharmacology

TRV130: A μ-Opioid Receptor-Biased Ligand

Scott M. DeWire, Dennis S. Yamashita, David H. Rominger, Guodong Liu, Conrad L. Cowan, Thomas M. Graczyk, Xiao-Tao Chen, Philip M. Pitis, Dimitar Gotchev, Catherine Yuan, Michael Koblish, Michael W. Lark and Jonathan D. Violin
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 708-717; DOI: https://doi.org/10.1124/jpet.112.201616

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Research ArticleNeuropharmacology

TRV130: A μ-Opioid Receptor-Biased Ligand

Scott M. DeWire, Dennis S. Yamashita, David H. Rominger, Guodong Liu, Conrad L. Cowan, Thomas M. Graczyk, Xiao-Tao Chen, Philip M. Pitis, Dimitar Gotchev, Catherine Yuan, Michael Koblish, Michael W. Lark and Jonathan D. Violin
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 708-717; DOI: https://doi.org/10.1124/jpet.112.201616
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