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An Effective and Safe Enkephalin Analog for Antinociception
K K DurgaRao Viswanadham1, Roland Böttger1, Lukas Hohenwarter1
1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Pharmaceutics
|July 2, 2021
Summary
A novel Leu-Enkephalin (Leu-ENK) analog, KK-103, demonstrates potent and long-lasting pain relief. This safer analgesic candidate shows promise in overcoming opioid-related side effects and overdose deaths.
Area of Science:
- Neuroscience
- Pharmacology
- Medicinal Chemistry
Background:
- Opioids cause significant global overdose deaths and adverse effects, necessitating safer analgesics.
- Endogenous opioid peptides like Leu-Enkephalin (Leu-ENK) have limited therapeutic utility due to poor stability and membrane permeability.
- Development of effective and safer pain management strategies is a critical unmet medical need.
Purpose of the Study:
- To design and synthesize novel Leu-Enkephalin analogs with improved pharmacokinetic properties and analgesic efficacy.
- To evaluate the binding affinity, stability, and in vivo analgesic activity of a lead analog, KK-103.
- To compare the safety profile of KK-103 with traditional opioids like morphine.
Main Methods:
- Synthesis of a focused library of Leu-ENK analogs with hydrophobic modifications.
- Assessment of delta opioid receptor binding affinity and plasma half-life of KK-103.
- Evaluation of analgesic efficacy using murine hot-plate and formalin pain models.
- Investigation of central nervous system activity and safety profile, including respiratory depression and dependence.
Main Results:
- The N-pivaloyl analog KK-103 exhibited high delta opioid receptor binding affinity and an extended plasma half-life of 37 hours.
- KK-103 demonstrated significantly enhanced analgesic efficacy (10-fold improvement) in the hot-plate model and reduced pain behaviors in the formalin model.
- Central nervous system action via opioid receptors was confirmed, with KK-103 showing prolonged effects without morphine-like adverse effects such as respiratory depression, dependence, or tolerance.
Conclusions:
- KK-103 represents a promising Leu-Enkephalin analog with superior stability, permeability, and analgesic potency.
- The developed analog exhibits a favorable safety profile, lacking key adverse effects associated with conventional opioids.
- KK-103 holds significant potential as a safer and more effective alternative analgesic for managing pain.
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