Combined Interactions with I₁-, I₂-Imidazoline Binding Sites and α₂-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 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.