Opioid peptide receptor studies. 17. Attenuation of chronic morphine effects after antisense oligodeoxynucleotide knock-down of RGS9 protein in cells expressing the cloned Mu opioid receptor

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.

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P.1.c.0511 Heterodimerization of mu opioid receptor and nociceptin/orphanin FQ peptide receptor alters g protein coupling

European Neuropsychopharmacology ◽

10.1016/s0924-977x(09)70411-0 ◽

2009 ◽

Vol 19 ◽

pp. S280-S281

Author(s):

O. Gunduz ◽

E. Baldini ◽

A. Borsodi ◽

S. Benyhe ◽

M. Corbani

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Mu Opioid Receptor ◽

Orphanin Fq ◽

G Protein Coupling ◽

Mu Opioid ◽

Protein Coupling ◽

Peptide Receptor

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Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal

Journal of Endocrinology ◽

10.1677/joe.1.06960 ◽

2006 ◽

Vol 191 (1) ◽

pp. 137-145 ◽

Cited By ~ 78

Author(s):

Yan Zhou ◽

Jacob Bendor ◽

Lauren Hofmann ◽

Matthew Randesi ◽

Ann Ho ◽

...

Keyword(s):

Opioid Receptor ◽

Lateral Hypothalamus ◽

Brain Regions ◽

Mu Opioid Receptor ◽

Morphine Withdrawal ◽

Mrna Levels ◽

Chronic Morphine ◽

Mu Opioid ◽

Morphine Administration ◽

Related Stress

In this study, we investigated the effects of acute morphine administration, chronic intermittent escalating-dose morphine administration and spontaneous withdrawal from chronic morphine on mRNA levels of mu opioid receptor (MOP-r), and the opioid peptides pro-opiomelanocortin (POMC) and preprodynorphin (ppDyn) in several key brain regions of the rat, associated with drug reward and motivated behaviors: lateral hypothalamus (lat.hyp), nucleus accumbens (NAc) core, amygdala, and caudate–putamen (CPu). There was no effect on MOP-r mRNA levels in these brain regions 30 min after either a single injection of morphine (10 mg/kg, i.p.) or chronic intermittent escalating-dose morphine (from 7.5 mg/kg per day on day 1 up to 120 mg/kg per day on day 10). Activation of the stress-responsive hypothalamic–pituitary–adrenal axis by 12 h withdrawal from chronic morphine was confirmed; both POMC mRNA levels in the anterior pituitary and plasma adrenocorticotropic hormone levels were significantly elevated. Under this withdrawal-related stress condition, there was an increase in MOP-r mRNA levels in the lat.hyp, NAc core, and CPu. Recent studies have demonstrated a novel role for the lat.hyp orexin (or hypocretin) activation in both drug-related positive rewarding, and withdrawal effects. Around 50% of lat.hyp orexin neurons express MOP-r. Therefore, we also examined the levels of lat.hyp orexin mRNA, and found them increased in morphine withdrawal, whereas there was no change in levels of the lat.hyp ppDyn mRNA, a gene coexpressed with the lat.hyp orexin. Our results show that there is an increase in MOP-r gene expression in a region-specific manner during morphine withdrawal, and support the hypothesis that increased lat.hyp orexin activity plays a role in morphine-withdrawal-related behaviors.

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Phosphorylation of unique C‐terminal sites of the mu‐opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine

Journal of Neurochemistry ◽

10.1111/jnc.14863 ◽

2019 ◽

Vol 152 (4) ◽

pp. 449-467 ◽

Cited By ~ 1

Author(s):

Sumita Chakrabarti ◽

Nai‐Jiang Liu ◽

Alan R. Gintzler

Keyword(s):

Opioid Receptor ◽

Mu Opioid Receptor ◽

Chronic Morphine ◽

Mu Opioid

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Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

10.1101/771246 ◽

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.

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