title: Combined Interactions with I1-, I2-Imidazoline Binding Sites and α2-Adrenoceptors To Manage Opioid Addiction.
abstract: Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including α2-adrenoceptors (α2-ARs) and I1- and I2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including α2-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I1-/I2-IBS or I1-/I2-IBS/α2-ARs. The compounds showing the highest affinities for I1-/I2-IBS or I1-/I2-IBS/α2-ARs have been selected for theirin vivoevaluation on opiate withdrawal syndrome. Interestingly,9, displaying I1-/I2-IBS/α2-ARs interaction profile, appears more effective in reducing expression and acquisition of morphine dependence and, therefore, might be considered a promising tool in managing opioid addiction.
authors: School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors: Maria Elena
authors: ME
authors: Giusepponi
authors: School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors: Carlo
authors: C
authors: Cifani
authors: School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors: Maria Vittoria
authors: MV
authors: Micioni Di Bonaventura
authors: School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors: Laura
authors: L
authors: Mattioli
authors: Department of Pharmacology, Medical Sciences Building, University of Alberta , Edmonton, Alberta T6G 2R3, Canada.
authors: Alan
authors: A
authors: Hudson
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Eleonora
authors: E
authors: Diamanti
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Fabio
authors: F
authors: Del Bello
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Mario
authors: M
authors: Giannella
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Valerio
authors: V
authors: Mammoli
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Corinne Dalila
authors: CD
authors: Paoletti
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Alessandro
authors: A
authors: Piergentili
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Maria
authors: M
authors: Pigini
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors: Wilma
authors: W
authors: Quaglia
keywords: agmatine biological profile; combined interactions; imidazolines; opioid addiction; α2-adrenoceptors