Opioid peptide receptor studies. 16. Chronic morphine alters G-protein function in cells expressing the cloned mu opioid receptor

Synapse ◽  
2002 ◽  
Vol 47 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Heng Xu ◽  
Yi-Feng Lu ◽  
Richard B. Rothman
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Protein Function ◽  
Opioid Peptide ◽  
Mu Opioid Receptor ◽  
Chronic Morphine ◽  
Mu Opioid ◽  
Peptide Receptor ◽  
In Cells

scholarly journals Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

2019 ◽  
Author(s):  
Parker W. de Waal ◽  
Jingjing Shi ◽  
Erli You ◽  
Xiaoxi Wang ◽  
Karsten Melcher ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
Opioid Receptor ◽  
Molecular Mechanisms ◽  
Opioid Peptide ◽  
Mu Opioid Receptor ◽  
Public Attention ◽  
Mu Opioid ◽  
Biased Signaling ◽  
Insight Into

AbstractThe development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or β-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent β-arrestin biased agonist, activates the μ-opioid receptor (μOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. We found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce β-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate a mechanism where the n-aniline ring of fentanyl mediates μOR β-arrestin through a novel M153 “microswitch” by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated β-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.Author SummaryThe global opioid crisis has drawn significant attention to the risks associated with over-use of synthetic opioids. Despite the public attention, and perhaps in-line with the profit-based incentives of the pharmaceutical industry, there is no public structure of mu-opioid receptor bound to fentanyl or fentayl derivatives. A publicly available structure of the complex would allow open-source development of safer painkillers and synthetic antagonists. Current overdose antidotes, antagonists, require natural products in their synthesis which persists a sizable barrier to market and develop better antidotes. In this work we use advance molecular dynamics techniques to obtain the bound geometry of mu-opioid receptor with fentanyl (and derivatives). Based on our in-silico structure, we synthesized and tested novel compounds to validate our predicted structure. Herein we report the bound state of several dangerous fentanyl derivatives and introduce new derivatives with signaling profiles that may lead to lower risk of respiratory depression.

Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Jeremy C. Cornelissen ◽  
Bruce E. Blough ◽  
Laura M. Bohn ◽  
S. Stevens Negus ◽  
Matthew L. Banks
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Rhesus Monkeys ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists ◽  
Male Rhesus

scholarly journals Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2087 ◽  
Author(s):  
Maria Dumitrascuta ◽  
Marcel Bermudez ◽  
Steven Ballet ◽  
Gerhard Wolber ◽  
Mariana Spetea
Keyword(s):  
Molecular Docking ◽  
Opioid Receptor ◽  
Rank Order ◽  
Opioid Peptide ◽  
Mu Opioid Receptor ◽  
In Vitro Assays ◽  
Peptide Ligand ◽  
Mu Opioid ◽  
Peptide Analogues

The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt1]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure–activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt1]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2′,6′-dimethyl-L-Tyr) moiety of [Dmt1]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand–MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.

scholarly journals A Computationally Designed Water-Soluble Variant of a G-Protein-Coupled Receptor: The Human Mu Opioid Receptor

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e66009 ◽  
Author(s):  
Jose Manuel Perez-Aguilar ◽  
Jin Xi ◽  
Felipe Matsunaga ◽  
Xu Cui ◽  
Bernard Selling ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Water Soluble ◽  
G Protein Coupled Receptor ◽  
Mu Opioid ◽  
G Protein Coupled
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