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Bioorg Med Chem. 2012 Apr 1;20(7):2259-65. doi: 10.1016/j.bmc.2012.02.016. Epub 2012 Feb 13.

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

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School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy.


Aim of the present study was to obtain novel α(2)-adrenoreceptor (α(2)-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α(2)-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 α(2A)-subtype. Moreover, 2 showed an affinity at I(2)-imidazoline binding sites (I(2)-IBS) comparable to that at α(2A)-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α(2A)-AR antagonism in the I(2)-IBS-mediated morphine analgesia enhancement.

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