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Abstract: We recently reported that the α2-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its α2C-AR agonism), was devoid of sedative side effects (due to its α2A-AR antagonism), prevented and reversed morphine tolerance and dependence. To highlight the molecular characteristics compatible with this behaviour and to obtain novel agents potentially useful in chronic pain and opioid addiction management, the allyl group of 9 was replaced by substituents of moderate steric bulk (MR) and positive or negative lipophilic (π) and electronic (σ) contributions in all the possible combinations. Effective novel α2C-agonists/α2A-antagonists (2, 3, 10, 12, and 17) were obtained. This study also demonstrated that contradictory combinations of the physicochemical parameters were similarly able to induce the α2A-activation. Since we had previously observed that the absolute configuration affected only the potency, but not the functional profile of the ligands, we hypothesized that the α2A-activation was governed by a ligand preferred conformation. From a structural overlay investigation it emerged that an extended conformation appeared to be associated with dual α2C-agonism/α2A-antagonism, whereas a folded conformation associated with α2C-/α2A-agonism. [Copyright &y& Elsevier]