Might the observed α2A-adrenoreceptor agonism or antagonism of allyphenyline analogues be ascribed to different molecular conformations?

We recently reported that the alpha(2)-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its alpha(2C)-AR agonism), was devoid of sedative side effects (due to its alpha(2A)-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 (pi) and electronic (sigma) contributions in all the possible combinations. Effective novel alpha(2C)-agonists/alpha(2A)-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 alpha(2A)-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 alpha(2A)-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 alpha(2C)-agonism/alpha(2A)-antagonism, whereas a folded conformation associated with alpha(2C)-/alpha(2A)-agonism. (C) 2012 Elsevier Ltd. All rights reserved.