Abstract
The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; the corresponding distomers are partial agonists. Because in clinical pain management with opioids α(2C)-AR agonists, devoid of the α(2A)-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing α(2C)-agonism/α(2A)-antagonism, have been studied in vivo. The data suggest that partial α(2C)-activation is compatible with effective enhancement of morphine analgesia and reduction both of morphine tolerance acquisition and morphine dependence acquisition and expression. On the contrary, full α(2C)-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(+)-4 has been found to be very unusual.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-2 Receptor Agonists / chemical synthesis*
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Adrenergic alpha-2 Receptor Agonists / chemistry
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Adrenergic alpha-2 Receptor Agonists / pharmacology
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Adrenergic alpha-2 Receptor Antagonists / chemical synthesis*
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Adrenergic alpha-2 Receptor Antagonists / chemistry
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Adrenergic alpha-2 Receptor Antagonists / pharmacology
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Allyl Compounds / chemical synthesis*
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Allyl Compounds / chemistry
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Allyl Compounds / pharmacology
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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CHO Cells
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Clonidine / pharmacology
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Cricetinae
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Cricetulus
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Drug Partial Agonism
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Drug Tolerance
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Humans
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Imidazolines / chemical synthesis*
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Imidazolines / chemistry
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Imidazolines / pharmacology
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Male
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Mice
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Morphine / pharmacology*
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Morphine Dependence / prevention & control*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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2-(1-(2-allylphenoxy)ethyl)-4,5-dihydro-1H-imidazole
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Adrenergic alpha-2 Receptor Agonists
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Adrenergic alpha-2 Receptor Antagonists
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Allyl Compounds
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Analgesics
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Imidazolines
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Morphine
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Clonidine