Abstract
The pharmaceutical potential of natural analgesic peptides is mainly hampered by their inability to cross the blood-brain barrier, BBB. Increasing peptide-cell membrane affinity through drug design is a promising strategy to overcome this limitation. To address this challenge, we grafted ibuprofen (IBP), a nonsteroidal anti-inflammatory drug, to kyotorphin (l-Tyr-l-Arg, KTP), an analgesic neuropeptide unable to cross BBB. Two new KTP derivatives, IBP-KTP (IbKTP-OH) and IBP-KTP-amide (IbKTP-NH(2)), were synthesized and characterized for membrane interaction, analgesic activity and mechanism of action. Ibuprofen enhanced peptide-membrane interaction, endowing a specificity for anionic fluid bilayers. A direct correlation between anionic lipid affinity and analgesic effect was established, IbKTP-NH(2) being the most potent analgesic (from 25 μmol · kg(-1)). In vitro, IbKTP-NH(2) caused the biggest shift in the membrane surface charge of BBB endothelial cells, as quantified using zeta-potential dynamic light scattering. Our results suggest that IbKTP-NH(2) crosses the BBB and acts by activating both opioid dependent and independent pathways.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / chemistry*
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Analgesics / metabolism
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Analgesics / therapeutic use
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Analgesics, Non-Narcotic / chemistry
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Analgesics, Non-Narcotic / metabolism
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Analgesics, Non-Narcotic / therapeutic use
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Analgesics, Opioid / antagonists & inhibitors
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Analgesics, Opioid / chemistry
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Analgesics, Opioid / metabolism
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Analgesics, Opioid / therapeutic use
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry*
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Anti-Inflammatory Agents, Non-Steroidal / metabolism
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Blood-Brain Barrier / metabolism*
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Brain / drug effects
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Brain / metabolism
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Cattle
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Cell Membrane / chemistry
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Cell Membrane / metabolism
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Cells, Cultured
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Cross-Linking Reagents / chemistry
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Drug Design
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Endorphins / chemistry*
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Endorphins / metabolism
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Endorphins / therapeutic use
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Humans
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Hydrophobic and Hydrophilic Interactions
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Ibuprofen / analogs & derivatives*
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Ibuprofen / chemistry
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Ibuprofen / metabolism
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Ibuprofen / therapeutic use
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Lipid Bilayers / chemistry
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Lipid Bilayers / metabolism
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Male
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Neurons / drug effects
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Neurons / metabolism
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Rats
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Rats, Wistar
Substances
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Analgesics
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Analgesics, Non-Narcotic
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Analgesics, Opioid
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Anti-Inflammatory Agents, Non-Steroidal
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Cross-Linking Reagents
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Endorphins
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Lipid Bilayers
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kyotorphin
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Ibuprofen