title: Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect.
abstract: 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.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Diamanti
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Mammoli
authors.affiliation: Aptuit Verona , via Fleming 4, 37135 Verona, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.affiliation: School of Pharmacy, Pharmacognosy Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mattioli
authors.affiliation: School of Pharmacy, Pharmacognosy Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Titomanlio
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Benedetti
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Varrone
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
keywords: 5-HT1A-R agonists; antidepressant-like effect; morphine withdrawal symptoms reduction; α2-adrenergic ligands