Abstract
We designed and synthesized pentacyclic propellane derivatives with a 6-amide side chain to afford compounds with higher MOR/KOR ratio and lower sedative effects than nalfurafine. The obtained etheno-bridged derivative with a β-amide side chain, YNT-854, showed a higher MOR/KOR ratio than nalfurafine. YNT-854 also exhibited a higher dose ratio between the sedative effect and the analgesic effect than observed with nalfurafine, which may guide the future design of useful analgesics with a weaker sedative effect than nalfurafine.
Keywords:
Analgesic; KOR selectivity; Nalfurafine; Opioid; Propellane.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemistry*
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Analgesics, Opioid / chemical synthesis*
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Analgesics, Opioid / metabolism
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Analgesics, Opioid / therapeutic use
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Guinea Pigs
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Male
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Mice
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Mice, Inbred ICR
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Morphinans / chemical synthesis*
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Morphinans / chemistry
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Morphinans / metabolism
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Morphinans / therapeutic use
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Pain / chemically induced
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Pain / drug therapy
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Protein Binding
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Receptors, Opioid, kappa / agonists
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Receptors, Opioid, kappa / metabolism
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Receptors, Opioid, mu / agonists
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Receptors, Opioid, mu / metabolism
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / chemistry
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Spiro Compounds / metabolism
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Spiro Compounds / therapeutic use
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Structure-Activity Relationship
Substances
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Amides
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Analgesics, Opioid
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Morphinans
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Receptors, Opioid, kappa
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Receptors, Opioid, mu
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Spiro Compounds
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YNT-854
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TRK 820