2013
DOI: 10.1124/jpet.112.201616
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A G Protein-Biased Ligand at theμ-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 b-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the m-opioid receptor (MOR) to G proteins, but not b-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 … Show more

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Cited by 542 publications
(631 citation statements)
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“…One very promising area for biased drug development involves G protein pathway-selective opioid receptor agonists (Dewire et al, 2013;Schmid et al, 2013;Zhou et al, 2013). From the initial discovery that the impaired m opioid receptor (MOR) desensitization observed in arrestin3 null mice led to enhanced morphine analgesia with less tolerance (Bohn et al, 1999(Bohn et al, , 2000, it was apparent that nondesensitizing opioid analogs might be superior analgesics.…”
Section: Translating Biasmentioning
confidence: 99%
“…One very promising area for biased drug development involves G protein pathway-selective opioid receptor agonists (Dewire et al, 2013;Schmid et al, 2013;Zhou et al, 2013). From the initial discovery that the impaired m opioid receptor (MOR) desensitization observed in arrestin3 null mice led to enhanced morphine analgesia with less tolerance (Bohn et al, 1999(Bohn et al, , 2000, it was apparent that nondesensitizing opioid analogs might be superior analgesics.…”
Section: Translating Biasmentioning
confidence: 99%
“…From the agonists used in the present study, only loperamide has been used clinically and is an effective antidiarrheal therapeutic. The G protein-biased MOR agonist TRV130 (Oliceridine) does not promote MOR endocytosis and clinical trial data suggest that this analgesic has diminished gastrointestinal side-effects in preclinical models (11). This highlights the potential translational relevance of studies of MOR trafficking and associated ligand bias in rodent species for the future development of OBD therapeutics.…”
Section: G260mentioning
confidence: 99%
“…2. The deemphasis of a debilitating cellular signal, such as elimination of b-arrestin signaling for opioid analgesics (Raehal et al, 2005;DeWire et al, 2013;Charfi et al, 2015) and the loss of b-arrestin-mediated dysphoric effects of k-opioid agonists (White et al, 2014). 3.…”
Section: Therapeutic Applications Of Signaling Biasmentioning
confidence: 99%