Adenosine is an endogenous purine nucleoside that modulates a variety of physiological functions as a result of its activation of specific G protein-coupled receptors defined as A1, A2A, A2B, and A3 adenosine receptors (ARs) (1). The A1 adenosine receptor (A1AR) is the best characterized adenosine receptor subtype. Selective A1AR agonists mediate neuro- and cardioprotective effects, reduce lipolysis in adipose tissue, and intraocular pressure in glaucoma (1,2). The A1AR is abundantly expressed in spinal cord and other neuronal tissue, and its activation produced pain-relieving effects in a number of preclinical animal models (3). Our previous works discovered that combining the appropriate 5- and N6-substitution in adenosine derivatives, highly selective human (h) A1AR agonists (4) or highly potent dual hA1AR agonists and hA3AR antagonists can be obtained (5). The substitution of OH at the 5-position of N6- substituted adenosine derivatives with a chlorine atom is not only well tolerated by the hA1AR but even improves the A1AR selectivity and affinity. 5-Chloro-5-deoxy-N6-(±)-endo-norbornyl- adenosine (5Cl5d-(±)-ENBA) turned out to be a potent and the most selective human and mouse (m) A1AR agonist vs A3AR so far known (4,6) with analgesic effects in a mouse model of neuropathic pain (7). Moreover, it was found to reduce the dyskinesia caused by L-DOPA in a mouse model of Parkinson disease (PD) (8) and the tremor in a harmaline-induced model of essential tremor (ET), suggesting that A1AR may be a potential target also for the treatment of ET (9). In order to explore novel combinations of 5-modification and N6-substitution leading to potent and selective A1AR agonists, a series of 5,N6-disubstituted adenosine derivatives was synthesized and evaluated for affinity and selectivity at all cloned hAR subtypes. References: 1. Jacobson, K. A.; Muller, C. E. Neuropharmacology 2016, 104, 31-49. 2. Donegan, R. K. and Lieberman, R. L. J. Med. Chem. 2016, 59, 788-809. 3. Sawynok, J. Adenosine receptor targets for pain. Neuroscience, 2016, 338, 1- 18. 4. 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. 5. Petrelli, R.; Torquati, I.; Kachler, S.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Lavecchia, A.; Klotz, K.- N.; Cappellacci, L. J. Med. Chem. 2015, 58, 2560-2566. 6. Carlin, J. L.; Jain, S.; Gizewski, E.; Wan, T. C.; Tosh, D. K.; Xiao, C.; Auchampach, J. A.; Jacobson, K. A.; Gavrilova, O.; Reitman, M. L. Neuropharmacology 2017, 114, 101-113. 7. 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. 8. 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. 9. Kosmowska, B.; Ossowska, K.; Glowacka, U.; Wardas, J. CNS Neurosci. Ther. 2017, DOI: 10.1111/cns.12692

Design, synthesis and biological evaluation of N6/5’-disubstituted adenosine derivatives as A1 adenosine receptor agonists

Mirko Scortichini;Riccardo Petrelli;Sabatino Maione;Loredana Cappellacci
2017-01-01

Abstract

Adenosine is an endogenous purine nucleoside that modulates a variety of physiological functions as a result of its activation of specific G protein-coupled receptors defined as A1, A2A, A2B, and A3 adenosine receptors (ARs) (1). The A1 adenosine receptor (A1AR) is the best characterized adenosine receptor subtype. Selective A1AR agonists mediate neuro- and cardioprotective effects, reduce lipolysis in adipose tissue, and intraocular pressure in glaucoma (1,2). The A1AR is abundantly expressed in spinal cord and other neuronal tissue, and its activation produced pain-relieving effects in a number of preclinical animal models (3). Our previous works discovered that combining the appropriate 5- and N6-substitution in adenosine derivatives, highly selective human (h) A1AR agonists (4) or highly potent dual hA1AR agonists and hA3AR antagonists can be obtained (5). The substitution of OH at the 5-position of N6- substituted adenosine derivatives with a chlorine atom is not only well tolerated by the hA1AR but even improves the A1AR selectivity and affinity. 5-Chloro-5-deoxy-N6-(±)-endo-norbornyl- adenosine (5Cl5d-(±)-ENBA) turned out to be a potent and the most selective human and mouse (m) A1AR agonist vs A3AR so far known (4,6) with analgesic effects in a mouse model of neuropathic pain (7). Moreover, it was found to reduce the dyskinesia caused by L-DOPA in a mouse model of Parkinson disease (PD) (8) and the tremor in a harmaline-induced model of essential tremor (ET), suggesting that A1AR may be a potential target also for the treatment of ET (9). In order to explore novel combinations of 5-modification and N6-substitution leading to potent and selective A1AR agonists, a series of 5,N6-disubstituted adenosine derivatives was synthesized and evaluated for affinity and selectivity at all cloned hAR subtypes. References: 1. Jacobson, K. A.; Muller, C. E. Neuropharmacology 2016, 104, 31-49. 2. Donegan, R. K. and Lieberman, R. L. J. Med. Chem. 2016, 59, 788-809. 3. Sawynok, J. Adenosine receptor targets for pain. Neuroscience, 2016, 338, 1- 18. 4. 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. 5. Petrelli, R.; Torquati, I.; Kachler, S.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Lavecchia, A.; Klotz, K.- N.; Cappellacci, L. J. Med. Chem. 2015, 58, 2560-2566. 6. Carlin, J. L.; Jain, S.; Gizewski, E.; Wan, T. C.; Tosh, D. K.; Xiao, C.; Auchampach, J. A.; Jacobson, K. A.; Gavrilova, O.; Reitman, M. L. Neuropharmacology 2017, 114, 101-113. 7. 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. 8. 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. 9. Kosmowska, B.; Ossowska, K.; Glowacka, U.; Wardas, J. CNS Neurosci. Ther. 2017, DOI: 10.1111/cns.12692
2017
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/405763
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