Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence

J Med Chem. 2010 Nov 11;53(21):7825-35. doi: 10.1021/jm100977d.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists / chemical synthesis*
  • Adrenergic alpha-2 Receptor Agonists / chemistry
  • Adrenergic alpha-2 Receptor Agonists / pharmacology
  • Adrenergic alpha-2 Receptor Antagonists / chemical synthesis*
  • Adrenergic alpha-2 Receptor Antagonists / chemistry
  • Adrenergic alpha-2 Receptor Antagonists / pharmacology
  • Allyl Compounds / chemical synthesis*
  • Allyl Compounds / chemistry
  • Allyl Compounds / pharmacology
  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • CHO Cells
  • Clonidine / pharmacology
  • Cricetinae
  • Cricetulus
  • Drug Partial Agonism
  • Drug Tolerance
  • Humans
  • Imidazolines / chemical synthesis*
  • Imidazolines / chemistry
  • Imidazolines / pharmacology
  • Male
  • Mice
  • Morphine / pharmacology*
  • Morphine Dependence / prevention & control*
  • Stereoisomerism
  • Structure-Activity Relationship


  • 2-(1-(2-allylphenoxy)ethyl)-4,5-dihydro-1H-imidazole
  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists
  • Allyl Compounds
  • Analgesics
  • Imidazolines
  • Morphine
  • Clonidine