Rational design and synthesis of new ligands directed to α2-Adrenergic receptors(α2-ARs) and I2-Imidazoline binding sites (IBS)\ud

Goal of this study was the synthesis of new structurally related imidazoline molecules direct to selectively interact with a2-Adrenoreceptors (a2-ARs) or I2-Imidazoline Binding Sites (I2-IBS). The rational design of these new compounds held in due consideration all the indications emerged by previous investigations, among them: i) the observation that essential requirement for α2-ARs/I2-IBS discrimination was the presence of an oxyethyl or ethylenic chain, respectively, between the aromatic portion and imidazoline nucleus; ii) the hypothesys that α2-ARs and I2-IBS could present analogies in the nature and orientation of some critical binding functions. The obtained ligands proved to be useful tools for the respective system characterization.\ud In both systems it was demonstrated that the introduction of pendent groups in the basic structure phenyl ring of some studied leads was able to induce a drastic change of their biological profile.\ud In fact, known α2-ARs antagonists, such as 1 and idazoxan, changed into efficient agonists, sometimes, endowed with significant α2C-AR selectivity (Section 1A).\ud Moreover, highlighting the critical role played by chirality in the activation of α2C-AR subtype, still defined enigmatic, it was showed that the ligand required stereochemical characteristics were strongly dependent on the nature of the pendent group in ortho position of the phenyl ring. In fact, a surprising reversal of enantioselectivity was observed for similar compounds biphenyline and m-nitro-biphenyline, whose preferred α2C configurations proved (S)-(-) and (R)-(+) forms, respectively (section 1B).\ud Many opiate drugs, such as morphine, are commonly used for pain relief, but their usefulness in prolonged use is limited by the development of tolerance and dependence. Since several studies indicated that the possible synergism with I2-IBS-mediated antinociceptive mechanisms could enhance the morphine analgesia and attenuate its side effects, new I2-IBS ligands have been prepared. All the new compounds displayed interesting I2-IBS affinity and significant I2-IBS selectivity with respect to I1-IBS and α2-ARs. As aforementioned, the introduction of substituents in the aromatic ring induced a significant change of biological profile. In fact, the compounds lacking in or endowed with pendent groups produced enhancement (positive modulation) or decrease (negative modulation), respectively, of morphine analgesia. Interestingly, both modulations appeared useful to attenuate the side effects development. In particular, phenyzoline (1, displaying positive modulation) and compound 9 (displaying negative modulation) proved able to significantly attenuate the development of tolerance and dependence, respectively (2A and 2B Sections). Finally, the comparative study of some rationally designed compounds pointed out some significant analogies between the hydrophobic domain of I2-IBS proteins binding site and aromatic cluster of α2C-AR binding site cavity.\ud \ud \ud \ud \u