Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence
| Autor: | Russell J. Thomas, Claudia Cardinaletti, Laura Mattioli, Mario Giannella, Fabio Del Bello, Ugo Zanelli, Marina Perfumi, Francesca Ghelfi, Michele Dal Cin, Maria Pigini, Wilma Quaglia, Alessandro Piergentili, Carla Marchioro |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Adrenergic CHO Cells Pharmacology Partial agonist Clonidine Mice Structure-Activity Relationship Cricetulus In vivo Cricetinae Drug Discovery medicine Adrenergic alpha-2 Receptor Agonists Animals Humans Agonism Imidazolines Analgesics Morphine Chemistry Morphine tolerance Stereoisomerism Drug Tolerance Adrenergic alpha-2 Receptor Antagonists Allyl Compounds Drug Partial Agonism Molecular Medicine Enantiomer Antagonism Morphine Dependence medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 53(21) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|