Favourable involvement of α2A-adrenoreceptor antagonism in the I2-imidazoline binding sites-mediated morphine analgesia enhancement

Aim of the present study was to obtain novel α2-adrenoreceptor (α2-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α2-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole α2A-subtype. Moreover, 2 showed an affinity at I2-imidazoline binding sites (I2-IBS) comparable to that at α2A-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α2A-AR antagonism in the I2-IBS-mediated morphine analgesia enhancement.