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ACS Med Chem Lett. 2016 Sep 8;7(10):956-961. eCollection 2016 Oct 13.

Combined Interactions with I1-, I2-Imidazoline Binding Sites and α2-Adrenoceptors To Manage Opioid Addiction.

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School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
Department of Pharmacology, Medical Sciences Building, University of Alberta , Edmonton, Alberta T6G 2R3, Canada.
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.


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 their in vivo evaluation 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.


agmatine biological profile; combined interactions; imidazolines; opioid addiction; α2-adrenoceptors

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