A G Protein-Biased Ligand at the μ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine

@article{Dewire2013AGP,
  title={A G Protein-Biased Ligand at the $\mu$-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine},
  author={Scott M Dewire and Dennis S. Yamashita and David H. Rominger and Guodong Liu and Conrad L. Cowan and Thomas M. Graczyk and Xiao-tao Chen and Philip M. Pitis and Dimitar B. Gotchev and Catherine C.K. Yuan and Michael Koblish and Michael W. Lark and Jonathan D. Violin},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2013},
  volume={344},
  pages={708 - 717}
}
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 β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the… 
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References

SHOWING 1-10 OF 74 REFERENCES

Morphine-like Opiates Selectively Antagonize Receptor-Arrestin Interactions*

Addictive opiates like morphine and oxymorphone exhibited large differences both at δ and μ receptors, which resulted in inhibition of short and long term events mediated by arrestin, such as rapid receptor internalization and down-regulation.

An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

Evaluating μOR trafficking in response to activation by a novel μ-selective agonist derived from the naturally occurring plant product, salvinorin A, finds that this compound, termed herkinorin, does not promote the recruitment of β-arrestin-2 to the μOR and does not lead to receptor internalization.

Agonist-Biased Signaling at the Histamine H4 Receptor: JNJ7777120 Recruits β-Arrestin without Activating G Proteins

It is demonstrated that JNJ7777120 recruits β-arrestin to the H4 receptor, independent of G protein activation, suggesting little difference in the levels of receptor reserve between the two assays.

Enhanced morphine analgesia in mice lacking beta-arrestin 2.

It is suggested that inhibition of beta-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence.

μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence

It is shown that in mice lacking β-arrestin-2, desensitization of the μ-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance.

Differential Association of Receptor-Gβγ Complexes with β-Arrestin2 Determines Recycling Bias and Potential for Tolerance of Delta Opioid Receptor Agonists

Data indicate that DORs may adopt ligand-specific conformations whose distinct recycling properties determine the extent of desensitization and are predictive of analgesic tolerance, and proposes that the development of functionally selective DOR ligands that favor recycling could constitute a valid strategy for the production of longer acting opioid analgesics.

Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

The 2.8 Å crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist is described, revealing high-resolution insights into opioid receptor structure that will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

A Dopamine D1 Receptor-Dependent β-Arrestin Signaling Complex Potentially Regulates Morphine-Induced Psychomotor Activation but not Reward in Mice

A potential role for a D1R-dependent βarr2/pERK signaling complex in selectively mediating the locomotor-stimulating but not the rewarding properties of morphine is suggested.

Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.

It is shown that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance.

Discovery of β-Arrestin–Biased Dopamine D2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

The results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects.
...