Aim of the present study was to obtain novel alpha(2)-adrenoreceptor (alpha(2)-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective alpha(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 alpha(2A)-subtype. Moreover, 2 showed an affinity at I-2-imidazoline binding sites (I-2-IBS) comparable to that at alpha(2A)-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of alpha(2A)-AR antagonism in the I-2-IBS-mediated morphine analgesia enhancement. (C) 2012 Elsevier Ltd. All rights reserved.
Mammoli, V., Bonifazi, A., Del Bello, F., Diamanti, E., Giannella, M., Hudson, A.L., et al. (2012). Favourable involvement of α2A-adrenoreceptor antagonism in the I₂-imidazoline binding sites-mediated morphine analgesia enhancement. BIOORGANIC & MEDICINAL CHEMISTRY, 20(7), 2259-2265 [10.1016/j.bmc.2012.02.016].
Favourable involvement of α2A-adrenoreceptor antagonism in the I₂-imidazoline binding sites-mediated morphine analgesia enhancement
Diamanti, Eleonora;
2012
Abstract
Aim of the present study was to obtain novel alpha(2)-adrenoreceptor (alpha(2)-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective alpha(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 alpha(2A)-subtype. Moreover, 2 showed an affinity at I-2-imidazoline binding sites (I-2-IBS) comparable to that at alpha(2A)-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of alpha(2A)-AR antagonism in the I-2-IBS-mediated morphine analgesia enhancement. (C) 2012 Elsevier Ltd. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
