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

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Del Bello F, Mattioli L, Ghelfi F, Giannella M, Piergentili A, Quaglia W, Cardinaletti C, Perfumi M, Thomas RJ, Zanelli U, Marchioro C, Dal Cin M, Pigini M

Fruitful adrenergic alpha(2C)-agonism/alpha(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.

PubMed ID

20925410 [ View in PubMed

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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 alpha(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 alpha(2C)-AR agonists, devoid of the alpha(2A)-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing alpha(2C)-agonism/alpha(2A)-antagonism, have been studied in vivo. The data suggest that partial alpha(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 alpha(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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Clonidine	Alpha-2A adrenergic receptor	EC 50 (nM)	8.32	N/A	N/A	Details
Clonidine	Alpha-2B adrenergic receptor	EC 50 (nM)	1174.9	N/A	N/A	Details
Clonidine	Alpha-2C adrenergic receptor	EC 50 (nM)	57.54	N/A	N/A	Details