Imidazoline nucleus as a biologically versatile scaffold

Several studies carried out in our laboratories demonstrated the biological versatility of the imidazoline nucleus and the crucial role played by the substituent in position 2 in affecting both the functional behaviour of the ligands and their recognition of a specific biological target. Indeed, suitable chemical manipulations of this substituent provided the antinociceptive agents homoazanicotine [1] or biphenyline [2], activating the α4β2- nicotinic receptor or the α2A-/α2C-adrenoreceptor (AR) subtypes, respectively. Similarly, the α2A-AR antagonist/α2C-AR agonist allyphenyline was obtained. It proved to be an efficacious adjuvant in morphine analgesia and was able to decrease morphine tolerance and dependence. Therefore, it may be considered a novel promising therapeutic tool in pain and opiod addiction management [3]. The imidazoline derivative idazoxan, a potent and non-selective α2-AR antagonist, also interacts with high affinity with I2-imidazoline binding sites (I2-IBS). Nevertheless, unlike other I2-IBS ligands, such as phenyzoline, it does not affect morphine analgesia nor inhibits the development of morphine tolerance [4,5]. Encouraged by our previous results, in the present study we designed some chemical manipulations of the idazoxan molecule with the aim to improve its I2-IBS behavioural profile and to obtain novel α2-AR subtype selective antagonists. Therefore, its quite planar 1,4-benzodioxane scaffold was replaced by the less conformationally constrained 1,4-dioxane nucleus substituted in position 5 or 6 with one phenyl group in both cis or trans stereochemical relationship with the imidazoline ring in position 2 (compounds 1-4). These modifications also allowed us to evaluate the influence of different distances between the aromatic and basic moieties on the biological effects and the stereochemical requirements of the receptor interactions. The obtained results supported the validity of our project. Indeed, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, maintained the I2-IBS recognition and was able to antagonize the sole α2A-AR subtype. Interestingly, due to its peculiar behaviour, 2 potently enhanced morphine analgesia, as shown in algesiometric tests. References [1] G. Ferretti, M. Dukat, M. Giannella et al., Bioorg. Med. Chem. Lett., 2000, 10, 2665-2668. [2] F. Gentili, P. Bousquet, L. Brasili et al., J. Med. Chem., 2002, 45, 32-40. [3] F. Del Bello, L. Mattioli, F. Ghelfi et al., J. Med. Chem., 2010, 53, 7825-7835. [4] F. Gentili, C. Cardinaletti, A. Carrieri et al., Eur. J. Pharmacol., 2006, 553, 73-81. [5] F. Gentili, C. Cardinaletti, C. Vesprini, et al., J. Med. Chem., 2008, 51, 5130-5134.