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Mu-opioid receptor selective superagonists produce prolonged respiratory depression
Nicholas J Malcolm1, Barbara Palkovic2, Daniel J Sprague1
1Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Iscience
|July 7, 2023
Summary
Synthetic nitazenes, like isotonitazene, are potent μ-opioid receptor (MOR) superagonists. This distinct signaling profile may predict prolonged respiratory depression, a dangerous characteristic for future opioid analgesic development.
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- Synthetic opioids, particularly nitazenes, pose a significant threat in the ongoing opioid epidemic.
- These compounds primarily target the μ-opioid receptor (MOR), a G protein-coupled receptor (GPCR), influencing G protein-dependent and β-arrestin signaling pathways.
Purpose of the Study:
- To investigate the GPCR signaling profiles of synthetic nitazenes, specifically isotonitazene and its metabolite.
- To determine if their potent MOR agonism correlates with severe respiratory depression.
Main Methods:
- Utilized a bioluminescence resonance energy transfer (BRET) system to analyze GPCR signaling.
- Assessed G protein and β-arrestin recruitment activity for isotonitazene and N-desethyl isotonitazene.
- Evaluated analgesic potency using mouse tail-flick assays and respiratory depression duration.
Main Results:
- Isotonitazene and N-desethyl isotonitazene demonstrated high potency as MOR-selective superagonists, exceeding DAMGO's activity in both G protein and β-arrestin pathways.
- Both compounds exhibited potent analgesia in mouse models.
- N-desethyl isotonitazene induced significantly longer-lasting respiratory depression compared to fentanyl.
Conclusions:
- Potent MOR-selective superagonism is a distinct pharmacological property of nitazenes.
- This superagonism may serve as a predictive marker for prolonged and potentially fatal respiratory depression.
- Further examination of this property is crucial for the development of safer opioid analgesics.
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