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An Effective and Safe Enkephalin Analog for Antinociception Viswanadham, K. K. DurgaRao; Böttger, Roland; Hohenwarter, Lukas; Nguyen, Anne; Rouhollahi, Elham; Smith, Alexander D.; Tsai, Yi-Hsuan; Chang, Yuan-Yu; Ortiz, Christopher Llynard; Yang, Lee-Wei; Jimenez, Liliana; Li, Siyuan; Hur, Chan; Li, Shyh-Dar
Abstract
Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.
Item Metadata
Title |
An Effective and Safe Enkephalin Analog for Antinociception
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Creator | |
Publisher |
Multidisciplinary Digital Publishing Institute
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Date Issued |
2021-06-22
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Description |
Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.
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Subject | |
Genre | |
Type | |
Language |
eng
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Date Available |
2021-08-06
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Provider |
Vancouver : University of British Columbia Library
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Rights |
CC BY 4.0
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DOI |
10.14288/1.0401242
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URI | |
Affiliation | |
Citation |
Pharmaceutics 13 (7): 927 (2021)
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Publisher DOI |
10.3390/pharmaceutics13070927
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty; Postdoctoral; Graduate; Other
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Rights URI | |
Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
CC BY 4.0