Adenosine is a regulatory nucleoside that can be generated in response to cellular stress and tissue damage as well as during episodes of tissue hypoxia or inflammation. It acts on specific G-protein coupled receptors that have been classified into four subtypes (A1, A2A, A2B and A3) on the basis of their structures and signal transduction systems. Selective A1 adenosine receptor (A1AR) agonists have antinociceptive, antiarrhythmic and neuro- and cardioprotective effects. There is a large body of evidence to suggest that A1AR agonists produce antinociception at spinal cord level as well as at supraspinal level. Our previous work showed that replacement of the 5′ -hydroxy-group by a chlorine atom in N6-substituted adenosine derivatives increased selectivity for A1AR [1]. 5′-Chloro-5′-deoxy-N6-(±)-(endo-norborn-2-yl)-adenosine (5′Cl5′d-(±)- ENBA) displayed high A1AR affinity and selectivity. It was shown to reduce both mechanical allodynia and thermal hyperalgesia in a mice model of neuropathic pain without affecting motor and cardiovascular functions [2]. Moreover, it reduced dyskinesia evoked by L-DOPA in a mice model of Parkinson’s disease [3]. In this work, novel N6/5’-disubstituted adenosine derivatives were synthesized and evaluated for analgesic activity in a formalin test in mice. The most potent compound of the series was found to inhibit the second phase of the nocifensive response induced by intrapaw injection of formalin at a dose of 2 mg/kg i.p. [2] Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393−2406. [3] (a) Luongo, L.; Petrelli, R.; Gatta, L.; Giordano, C.; Guida, F.; Vita, P.; Franchetti, P.; Grifantini, M.; De Novellis, V.; Cappellacci, L.; Maione, S. Molecules 2012, 17, 13712−13726. (b) Luongo, L.; Guida, F.; Imperatore, R.; Napolitano, F.; Gatta, L.; Cristino, L.; Giordano, C.; Siniscalco, D.; Di Marzo, V.; Bellini, G.; Petrelli, R.; Cappellacci, L.; Usiello, A.; de Novellis, V.; Rossi, F.; Maione, S. Glia 2014, 62, 122−132. [4] Mango, D.; Bonito-Oliva, A.; Ledonne, A.; Cappellacci, L.; Petrelli, R.; Nisticò, R.; Berretta, N.; Fisone, G.; Mercuri, N.B. Exp. Neurol. 2014, 261, 733−743.

Novel N6/5’-Disubstituted Adenosine Derivatives As A1 Adenosine Receptor Agonists: Synthesis, Binding Assay And Antinociceptive Activity

PETRELLI, Riccardo;TORQUATI, ILARIA;CAPPELLACCI, Loredana
2015-01-01

Abstract

Adenosine is a regulatory nucleoside that can be generated in response to cellular stress and tissue damage as well as during episodes of tissue hypoxia or inflammation. It acts on specific G-protein coupled receptors that have been classified into four subtypes (A1, A2A, A2B and A3) on the basis of their structures and signal transduction systems. Selective A1 adenosine receptor (A1AR) agonists have antinociceptive, antiarrhythmic and neuro- and cardioprotective effects. There is a large body of evidence to suggest that A1AR agonists produce antinociception at spinal cord level as well as at supraspinal level. Our previous work showed that replacement of the 5′ -hydroxy-group by a chlorine atom in N6-substituted adenosine derivatives increased selectivity for A1AR [1]. 5′-Chloro-5′-deoxy-N6-(±)-(endo-norborn-2-yl)-adenosine (5′Cl5′d-(±)- ENBA) displayed high A1AR affinity and selectivity. It was shown to reduce both mechanical allodynia and thermal hyperalgesia in a mice model of neuropathic pain without affecting motor and cardiovascular functions [2]. Moreover, it reduced dyskinesia evoked by L-DOPA in a mice model of Parkinson’s disease [3]. In this work, novel N6/5’-disubstituted adenosine derivatives were synthesized and evaluated for analgesic activity in a formalin test in mice. The most potent compound of the series was found to inhibit the second phase of the nocifensive response induced by intrapaw injection of formalin at a dose of 2 mg/kg i.p. [2] Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393−2406. [3] (a) Luongo, L.; Petrelli, R.; Gatta, L.; Giordano, C.; Guida, F.; Vita, P.; Franchetti, P.; Grifantini, M.; De Novellis, V.; Cappellacci, L.; Maione, S. Molecules 2012, 17, 13712−13726. (b) Luongo, L.; Guida, F.; Imperatore, R.; Napolitano, F.; Gatta, L.; Cristino, L.; Giordano, C.; Siniscalco, D.; Di Marzo, V.; Bellini, G.; Petrelli, R.; Cappellacci, L.; Usiello, A.; de Novellis, V.; Rossi, F.; Maione, S. Glia 2014, 62, 122−132. [4] Mango, D.; Bonito-Oliva, A.; Ledonne, A.; Cappellacci, L.; Petrelli, R.; Nisticò, R.; Berretta, N.; Fisone, G.; Mercuri, N.B. Exp. Neurol. 2014, 261, 733−743.
2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/391497
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