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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 2 -adrenoceptors (α 2 -ARs) and I 1 - and I 2 -imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including α 2 -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 1 -/I 2 -IBS or I 1 -/I 2 -IBS/α 2 -ARs. The compounds showing the highest affinities for I 1 -/I 2 -IBS or I 1 -/I 2 -IBS/α 2 -ARs have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, 9 , displaying I 1 -/I 2 -IBS/α 2 -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.

Pharmacological studies have suggested that I1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I1-agonists, devoid of the side effects associated with the common hypotensive α2-adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I1-profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I1 proteins.