Might adrenergic α2C-agonist/α2A-antagonist become a novel therapeutic multitarget tool for morphine chronic treatment of pain?

α2-Adrenoreceptor subtypes (α2A-, α2B-, α2C-AR), belonging to the superfamily of G-protein-coupled receptors, govern specific functions and are considered attractive targets for the treatment of various diseases. Nevertheless, the therapeutic utility of the so far employed ligands, is limited by their lack of subtype-selectivity. Interestingly, we obtained potent and selective α2C agonists by introduction of aliphatic substituents of moderate steric hindrance into the ortho position of the aromatic ring of the antagonist 2-(1-phenoxyethyl)-4,5-dihydro-1-H-imidazole. These compounds also behaved as antagonists at α2A-AR. Based on the knowledge that α2C subtype can contribute to spinal α2-agonist-mediated analgesia and adrenergic opioid sinergy1 and on the recent hypothesis that α2A-AR selective antagonists may offer a novel mechanism to augment the antinociceptive actions of partial opioid agonists,2 analgesia and morphine analgesia modulation of some of our compounds were evaluated by the mouse tail-flik test. We observed a strengthening of morphine analgesia ten-folds higher than that produced by the not subtype-seòlective α2-AR agonist clonidine, included in this study for useful comparison. 1. Fairbanks, C. A. et al., Pharmacol. Exp. Ther. 2002, 300, 282/290. 2. Özdogan, Ü. K. et al., Eur. J. Pharmacol. 2006, 529, 105-113.