Neuropathic pain, defined as “pain caused by a lesion or dysfunction of the nervous system”, is a personally devastating and costly condition affecting 3-8% of the population in developed countries. It may results from a wide variety of causes (including degenerative spinal disease, diabetes cancer and various infection diseases), that affect the brain, spinal cord and/or peripheral nerves. Existing treatments have limited effectiveness, being effective in some, but not all, neuropathic pain syndromes and producing relatively frequent adverse effects. Today’s first-line treatment of neuropathic pain relies predominantly on anticonvulsivant and antidepressant drugs, future pharmacological therapy may depend on agents that act on different targets. Adenosine is the endogenous agonist of four members of G-protein-coupled receptors (A1, A2A, A2B and A3 adenosine receptors, ARs) and has a wide range of biological effects. There is growing evidence that AR agonists are attractive therapeutic agents for a number of conditions including pain, cardiac arrhythmias, myocardial perfusion imaging, cardiac ischemia, inflammation and certain types of cancer. The A1 adenosine receptor (A1AR) is abundantly expressed in spinal cord and other neuronal tissues. There is evidence that A1AR agonists produce antinociception at the spinal cord as well as at supraspinal level (1). We have previously reported that 5’-chloro-5’-deoxy-N6-(±)-(endo-norborn-2-yl)-adenosine (5’Cl5'd-(±)-ENBA) has emerged as a potent and highly selective full agonist of human A1AR (hA1AR (Ki) = 0.51 nM, hA2AAR = 1,340 nM, hA2BAR = 2,740 nM, hA3AR = 1,290 nM) (2). Moreover, 5’Cl5’d-(±)-ENBA showed acute nocifensive effect in the formalin test and anti-neuropathic properties in a model of neuropathic pain, the spared nerve injury (SNI) of the sciatic nerve in mice (3). Interestingly, 5’Cl5’d-(±)-ENBA did not modify motor coordination and blood pressure or heart rate in unanaesthetized sham and SNI mice. The interesting biological properties of 5’Cl5’d-(±)-ENBA demonstrated that the substitution of 5’-hydroxyl group in adenosine analogues with a chlorine is well tolerated by A1AR, and seems reduce the cardiovascular side effects of A1AR full agonists. As a proof of the concept, 5’-chloro-5’-deoxy-N6-substituted adenosine/2-chloro-adenosine derivatives were synthesized and evaluated for affinity and selectivity at all human adenosine receptor subtypes. Moreover, antinociceptive activity in a formalin test in mice was assayed. The results of these studies will be discussed. (1) Sowa, N.A.; Voss, M.K.; Zylka, M.J. Mol. Pain 2010, 6, 2–8. (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) 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.

5’-CHLORO-5’-DEOXY-N6-SUBSTITUTED ADENOSINE DERIVATIVES: SYNTHESIS, ADENOSINE RECEPTOR AFFINITY AND ANTINOCICEPTIVE ACTIVITY

PETRELLI, Riccardo;TORQUATI, ILARIA;VITA, PATRIZIA;FRANCHETTI, Palmarisa;GRIFANTINI, Mario;CAPPELLACCI, Loredana
2013-01-01

Abstract

Neuropathic pain, defined as “pain caused by a lesion or dysfunction of the nervous system”, is a personally devastating and costly condition affecting 3-8% of the population in developed countries. It may results from a wide variety of causes (including degenerative spinal disease, diabetes cancer and various infection diseases), that affect the brain, spinal cord and/or peripheral nerves. Existing treatments have limited effectiveness, being effective in some, but not all, neuropathic pain syndromes and producing relatively frequent adverse effects. Today’s first-line treatment of neuropathic pain relies predominantly on anticonvulsivant and antidepressant drugs, future pharmacological therapy may depend on agents that act on different targets. Adenosine is the endogenous agonist of four members of G-protein-coupled receptors (A1, A2A, A2B and A3 adenosine receptors, ARs) and has a wide range of biological effects. There is growing evidence that AR agonists are attractive therapeutic agents for a number of conditions including pain, cardiac arrhythmias, myocardial perfusion imaging, cardiac ischemia, inflammation and certain types of cancer. The A1 adenosine receptor (A1AR) is abundantly expressed in spinal cord and other neuronal tissues. There is evidence that A1AR agonists produce antinociception at the spinal cord as well as at supraspinal level (1). We have previously reported that 5’-chloro-5’-deoxy-N6-(±)-(endo-norborn-2-yl)-adenosine (5’Cl5'd-(±)-ENBA) has emerged as a potent and highly selective full agonist of human A1AR (hA1AR (Ki) = 0.51 nM, hA2AAR = 1,340 nM, hA2BAR = 2,740 nM, hA3AR = 1,290 nM) (2). Moreover, 5’Cl5’d-(±)-ENBA showed acute nocifensive effect in the formalin test and anti-neuropathic properties in a model of neuropathic pain, the spared nerve injury (SNI) of the sciatic nerve in mice (3). Interestingly, 5’Cl5’d-(±)-ENBA did not modify motor coordination and blood pressure or heart rate in unanaesthetized sham and SNI mice. The interesting biological properties of 5’Cl5’d-(±)-ENBA demonstrated that the substitution of 5’-hydroxyl group in adenosine analogues with a chlorine is well tolerated by A1AR, and seems reduce the cardiovascular side effects of A1AR full agonists. As a proof of the concept, 5’-chloro-5’-deoxy-N6-substituted adenosine/2-chloro-adenosine derivatives were synthesized and evaluated for affinity and selectivity at all human adenosine receptor subtypes. Moreover, antinociceptive activity in a formalin test in mice was assayed. The results of these studies will be discussed. (1) Sowa, N.A.; Voss, M.K.; Zylka, M.J. Mol. Pain 2010, 6, 2–8. (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) 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.
2013
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275
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/324585
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