Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

@article{Melief2011DurationOA,
  title={Duration of Action of a Broad Range of Selective $\kappa$-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation},
  author={E. Melief and M. Miyatake and F. Carroll and C. B{\'e}guin and W. Carlezon and B. Cohen and S. Grimwood and C. Mitch and L. Rorick-Kehn and C. Chavkin},
  journal={Molecular Pharmacology},
  year={2011},
  volume={80},
  pages={920 - 929}
}
The κ-opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective κ-opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we… Expand
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References

SHOWING 1-10 OF 53 REFERENCES
Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal Kinase*
Norbinaltorphimine (NorBNI), guanidinonaltrindole, and atrans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine (JDTic) are selective κ opioid receptor (KOR) antagonists having very long durations ofExpand
Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling
TLDR
It is found that the μ-opioid receptor (MOR) could be similarly inactivated by a specific ligand class including the prototypical opioid, morphine, and acute analgesic tolerance to morphine and related opioids was blocked by JNK inhibition, but not by G protein receptor kinase 3 knockout. Expand
Identification of short-acting κ-opioid receptor antagonists with anxiolytic-like activity.
TLDR
Findings indicate that persistent inhibition is not an inherent property of κ-opioid-selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model, and supports λ-opIOid receptor as a promising target for developing novel psychiatric medications. Expand
Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase.
TLDR
Results suggest that the long duration KOR antagonists disrupt KOR signaling by activating JNK, and both norBNI and JDTic were found to stimulate c-Jun N-terminal kinase (JNK) phosphorylation in HEK293 cells expressing KOR-GFP but not in untransfected cells. Expand
Kappa opioid antagonist effects of the novel kappa antagonist 5′-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys
TLDR
Results suggest that 5′-Guanidinonaltrindole is a potent and selective kappa antagonist with a slow onset and long duration of action in rhesus monkeys. Expand
Pharmacological properties of JDTic: a novel κ-opioid receptor antagonist
Abstract Biological studies were conducted on (3 R )-7-Hydroxy- N -{(1 S )-1-{[(3 R ,4 RExpand
Phosphorylation of a Carboxyl-terminal Serine within the κ-Opioid Receptor Produces Desensitization and Internalization*
TLDR
It is demonstrated that GRK-mediated phosphorylation of serine 369 mediates rat KOR desensitization and internalization. Expand
Effectiveness of analogs of the kappa opioid receptor antagonist (3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) to reduce U50,488-induced diuresis and stress-induced cocaine reinstatement
TLDR
The failure of stress to reinstate cocaine seeking in rats treated with RTI-194 is consistent with results reported with J DTic, although it had less efficacy in lowering response levels than JDTic, suggesting a diminished overall effectiveness relative to it. Expand
Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist.
TLDR
JDTic is the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds and fails to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonists. Expand
Characterization of serotonin 5-hydroxytryptamine-1A receptor activation using a phospho-extracellular-signal regulated kinase 2 sensor.
TLDR
The results demonstrate the value of using ERK activation as a downstream sensor for GPCR function, providing an attractive complement to upstream endpoints such as ligand occupancy and binding of GTPgammaS. Expand
...
1
2
3
4
5
...