Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including alpha(2)-adrenoceptors (alpha(2)-ARs) I-1- and and I-2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including alpha(2)-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I-1-/I-2-IBS or I,/I-2-IBS/alpha(2)-ARs. The compounds showing the highest affinities for I-1-/I-2- IBS or I-1-/I-2-IBS/alpha(2)-ARs have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, 9, displaying I-1-/I-2-IBS/alpha(2)-ARs interaction profile, appears more effective in reducing expression and acquisition of morphine dependence and, therefore, might be considered a promising tool in managing opioid addiction.
Giusepponi, M.E., Cifani, C., Micioni Di Bonaventura, M.V., Mattioli, L., Hudson, A., Diamanti, E., et al. (2016). Combined Interactions with I1-, I2-Imidazoline Binding Sites and α2-Adrenoceptors To Manage Opioid Addiction. ACS MEDICINAL CHEMISTRY LETTERS, 7(10), 956-961 [10.1021/acsmedchemlett.6b00290].
Combined Interactions with I1-, I2-Imidazoline Binding Sites and α2-Adrenoceptors To Manage Opioid Addiction
Diamanti, Eleonora;
2016
Abstract
Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including alpha(2)-adrenoceptors (alpha(2)-ARs) I-1- and and I-2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including alpha(2)-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I-1-/I-2-IBS or I,/I-2-IBS/alpha(2)-ARs. The compounds showing the highest affinities for I-1-/I-2- IBS or I-1-/I-2-IBS/alpha(2)-ARs have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, 9, displaying I-1-/I-2-IBS/alpha(2)-ARs interaction profile, appears more effective in reducing expression and acquisition of morphine dependence and, therefore, might be considered a promising tool in managing opioid addiction.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
