A First‐in‐Human Clinical Study With TRV734, an Orally Bioavailable G‐Protein–Biased Ligand at the μ‐Opioid Receptor

2019 ◽  
Vol 9 (2) ◽  
pp. 256-266 ◽  
Author(s):  
Ian E. James ◽  
Franck Skobieranda ◽  
David G. Soergel ◽  
Kimberly A. Ramos ◽  
Dennis Ruff ◽  
...  
Keyword(s):  
Clinical Study ◽  
G Protein ◽  
Opioid Receptor ◽  
Μ Opioid Receptor ◽  
Orally Bioavailable ◽  
Human Clinical Study

scholarly journals A G protein signaling-biased agonist at the μ-opioid receptor reverses morphine tolerance while preventing morphine withdrawal

2019 ◽  
Vol 45 (2) ◽  
pp. 416-425 ◽  
Author(s):  
Travis W. Grim ◽  
Cullen L. Schmid ◽  
Edward L. Stahl ◽  
Fani Pantouli ◽  
Jo-Hao Ho ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Morphine Tolerance ◽  
Morphine Withdrawal ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Μ Opioid Receptor ◽  
Biased Agonist

scholarly journals Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor

2020 ◽  
Vol 41 (12) ◽  
pp. 947-959 ◽  
Author(s):  
Alexander Gillis ◽  
Andrea Kliewer ◽  
Eamonn Kelly ◽  
Graeme Henderson ◽  
Macdonald J. Christie ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Critical Assessment ◽  
Biased Agonism ◽  
Μ Opioid Receptor

scholarly journals Pharmacological Characters of Oliceridine, a μ-Opioid Receptor G-Protein–Biased Ligand in Mice

2019 ◽  
Vol 129 (5) ◽  
pp. 1414-1421 ◽  
Author(s):  
De-Yong Liang ◽  
Wen-Wu Li ◽  
Chinwe Nwaneshiudu ◽  
Karen-Amanda Irvine ◽  
J. David Clark
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Μ Opioid Receptor

scholarly journals Absence of G-protein activation by μ-opioid receptor agonists in the spinal cord of μ-opioid receptor knockout mice

1999 ◽  
Vol 126 (2) ◽  
pp. 451-456 ◽  
Author(s):  
Minoru Narita ◽  
Hirokazu Mizoguchi ◽  
Michiko Narita ◽  
Ichiro Sora ◽  
George R Uhl ◽  
...  
Keyword(s):  
Spinal Cord ◽  
G Protein ◽  
Opioid Receptor ◽  
Knockout Mice ◽  
Protein Activation ◽  
Receptor Agonists ◽  
G Protein Activation ◽  
Μ Opioid Receptor ◽  
Opioid Receptor Agonists

scholarly journals Live Cell Monitoring of μ-Opioid Receptor-mediated G-protein Activation Reveals Strong Biological Activity of Close Morphine Biosynthetic Precursors

2007 ◽  
Vol 282 (37) ◽  
pp. 27126-27132 ◽  
Author(s):  
Viacheslav O. Nikolaev ◽  
Chotima Boettcher ◽  
Christian Dees ◽  
Moritz Bünemann ◽  
Martin J. Lohse ◽  
...  
Keyword(s):  
Biological Activity ◽  
G Protein ◽  
Opioid Receptor ◽  
Live Cell ◽  
Protein Activation ◽  
G Protein Activation ◽  
Cell Monitoring ◽  
Μ Opioid Receptor

scholarly journals Selective Interference of β-Arrestin 1 with κ and δ but Not μ Opioid Receptor/G Protein Coupling

1998 ◽  
Vol 273 (38) ◽  
pp. 24328-24333 ◽  
Author(s):  
Zhi-Jie Cheng ◽  
Qing-Ming Yu ◽  
Ya-Lan Wu ◽  
Lan Ma ◽  
Gang Pei
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Selective Interference ◽  
Μ Opioid Receptor

scholarly journals Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation

2020 ◽  
Vol 21 (13) ◽  
pp. 4699 ◽  
Author(s):  
Zhennan Zhao ◽  
Tingting Huang ◽  
Jiazhong Li
Keyword(s):  
Molecular Dynamics ◽  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Conformational Changes ◽  
Opioid Analgesics ◽  
Dynamics Simulation ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros–Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR–ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

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