Allyphenyline analogues potentially useful in the management of chronic pain and opioid addiction.

We have previously demonstrated that α2-adrenergic (α2-AR) molecules, related to the non-subtype selective antagonist 1, displayed different activity at α2A-, α2B- and α2C-AR subtypes, depending on the peculiar nature of the ortho substituent in the Ar ring. For example, phenyl and thienyl groups converted 1 into the efficacious agonists 2 (biphenyline) and 3, respectively, activating α2A- and α2C-subtypes. Allyl or cyclopropyl groups of lower steric bulk turned the biological profile of the antagonist 1 only at α2C-subtype: 4 (allyphenyline) and 5 were potent α2C-agonists, whereas efficiently antagonized α2A-AR. From in vivo study 4 significantly enhanced morphine analgesia (due to α2C-AR agonism), was devoid of sedative side effects (due to α2A-AR antagonism) as well as prevented and contrasted morphine tolerance and dependence at very low dose (0.05 mg/Kg) [1]. Encouraged by these results, we prepared and studied compounds 6-12 inspired by 4. They were characterized by ortho substituents of moderate steric bulk and positive or negative σ and π contributions in all the combinations. A molecular modeling study performed on 2-12 highlighted that the desidered α2C-agonism/α2A-antagonism combination was displayed by ligands having favoured extended conformation (i.e. 4 and 5). In contrast, the activation of both α2A- and α2C-subtypes was produced by ligands endowed with favoured folded conformation (i.e. 2 and 3). [1] F. Del Bello et al. J. Med. Chem. 53, 2010, 7825-7835 and references therein.