Combined Interactions with I-, I-Imidazoline Binding Sites and α-Adrenoceptors To Manage Opioid Addiction.

Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including α-adrenoceptors (α-ARs) and I- and I-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including α-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 I-/I-IBS or I-/I-IBS/α-ARs. The compounds showing the highest affinities for I-/I-IBS or I-/I-IBS/α-ARs have been selected for their evaluation on opiate withdrawal syndrome. Interestingly, , displaying I-/I-IBS/α-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.