Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and non-opioid systems, including α2-adrenoceptors (α2-ARs) and I1- and I2-Imidazoline binding sites (IBS) (1). Agmatine, one of the hypothesized endogenous ligands of IBS, targets these systems and, acting as a multitarget agent, also exerts its modulatory action at many other targets (2). Therefore, anxiolitic, antidepressant, antinociceptive, anticonvulsive, antiproliferative and neuroprotective effects characterize its pharmacological profile. Recently, a significant number of studies suggests that agmatine and, in general, molecules displaying high affinity for α2–ARs and IBS are able to regulate opioid-induced analgesia (3) and to attenuate the development of tolerance and dependence (4). Attracted by the complex pharmacological profile of agmatine and considering the nature of its targets, we synthesized and studied two series of imidazoline molecules, rationally designed to produce simultaneous I1-/I2-IBS (1-4) and I1-/I2-IBS/2-ARs (5-9) interactions. Our aim was to obtain useful compounds for exploring the biological effects modulated by these target interaction combinations and to discover novel potential therapeutic tools. Therefore, compounds 1 and 5, showing the highest affinities for I1-/I2-IBS and I1-/I2-IBS/2-ARs, respectively, have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, both of them significantly affected expression and acquisition of morphine dependence, and, therefore, might be considered promising tools potentially useful in managing opioid addiction.

NOVEL IMIDAZOLINE MOLECULES INSPIRED BY THE PHARMACOLOGICAL PROFILE OF AGMATINE AS POTENTIAL TOOLS IN MANAGING OPIOID ADDICTION

GIUSEPPONI, MARIA ELENA;CIFANI, Carlo;MICIONI DI BONAVENTURA, Maria Vittoria;DEL BELLO, FABIO;GIANNELLA, Mario;MAMMOLI, VALERIO;PIERGENTILI, Alessandro;QUAGLIA, Wilma
2016-01-01

Abstract

Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and non-opioid systems, including α2-adrenoceptors (α2-ARs) and I1- and I2-Imidazoline binding sites (IBS) (1). Agmatine, one of the hypothesized endogenous ligands of IBS, targets these systems and, acting as a multitarget agent, also exerts its modulatory action at many other targets (2). Therefore, anxiolitic, antidepressant, antinociceptive, anticonvulsive, antiproliferative and neuroprotective effects characterize its pharmacological profile. Recently, a significant number of studies suggests that agmatine and, in general, molecules displaying high affinity for α2–ARs and IBS are able to regulate opioid-induced analgesia (3) and to attenuate the development of tolerance and dependence (4). Attracted by the complex pharmacological profile of agmatine and considering the nature of its targets, we synthesized and studied two series of imidazoline molecules, rationally designed to produce simultaneous I1-/I2-IBS (1-4) and I1-/I2-IBS/2-ARs (5-9) interactions. Our aim was to obtain useful compounds for exploring the biological effects modulated by these target interaction combinations and to discover novel potential therapeutic tools. Therefore, compounds 1 and 5, showing the highest affinities for I1-/I2-IBS and I1-/I2-IBS/2-ARs, respectively, have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, both of them significantly affected expression and acquisition of morphine dependence, and, therefore, might be considered promising tools potentially useful in managing opioid addiction.
2016
0000000000
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/399411
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