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ACS Med Chem Lett. 2012 Jun 8;3(7):535-9. doi: 10.1021/ml300064v. eCollection 2012 Jul 12.

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect.

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School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
Aptuit Verona , via Fleming 4, 37135 Verona, Italy.
School of Pharmacy, Pharmacognosy Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.


This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(-)-2 and (S)-(+)-2, displaying α2C-adrenoreceptor (AR) agonism/α2A-AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT1A receptor (5-HT1A-R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as α2C-AR agonists/α2A-AR antagonists/5-HT1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction.


5-HT1A-R agonists; antidepressant-like effect; morphine withdrawal symptoms reduction; α2-adrenergic ligands

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