Fruitful Adrenergic alpha(2C)-Agonism/alpha(2A)-Antagonism Combination to Prevent and Contrast Morphine Tolerance and Dependence

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 alpha2C-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 alpha2C-AR agonists, devoid of the alpha2A-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing alpha2C-agonism/alpha2Aantagonism, have been studied in vivo. The data suggest that partial alpha2C-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 alpha2C-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(þ)-4 has been found to be very unusual.