Adenosine is an endogenous purine ribonucleoside implicated in the control of the function of many tissues and organs. It exerts a protective action throughout all organs of the body and plays an important role not only in the pathophysiological processes, but also in the modulation of normal processes. Adenosine exerts its effects by interacting with specific G-protein coupled receptors, classified in 4 subtypes: A1, A2A, A2B and A3 (1). A1 adenosine receptor (A1AR) is widely distributed throughout the brain but also in the heart, aorta, liver kidney, bladder and eye. A1AR agonists have shown neuro- and cardioprotective effects, but their clinical use is hampered by severe cardiovascular side effects. A3AR are expressed in multiple organs and at low levels in the CNS. A3AR agonists are in clinical trials for the treatment of cancer and inflammatory diseases, and recent preclinical studies reported their analgesic effects in chronic neuropathic pain (2). Our previous work showed that potent dual A1AR agonists and A3AR antagonists have been obtained combining a 5'-C-ethyl-tetrazolyl moiety and an appropriate N6-substitution in adenosine derivatives (3). A dual A1 agonist and A3 antagonist might be useful in the treatment of glaucoma and other diseases, and might have advantages respect to the combination of two drugs. In order to study the influence of N6-substitution on affinity and selectivity at ARs, a novel series of 5'-C-2-ethyl-tetrazolyl-N6-substituted adenosine derivatives were synthesized and assayed at all human adenosine receptor subtypes. The results of this study will be discussed. (1) Fredholm, B.B.; Ijzerman, A.P.; Jacobson, K:A., Linden, J.; Muller, C.E. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and calssification of adenosine receptors - an update. Pharmacol. Rev. 2011, 63, 1-34. (2) Little, J.W.; Ford, A.; Symons-Liguori, A.M.; Chen, Z.; Janes, K.; Doyle, T.; Xie, J.; Luongo,, L.; Tosh, D.K.; Maione, S.; Bannister, K.; Dickenson, A.; Vandrah, T.W.; Porreca, F.; Jacobson, K.A.; Salvemini, D. Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 2015, 138, 28-35 (3) Petrelli, R.; Torquati, I.; Kachler, S.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Lavecchia, A.; Klotz, K.-N-; Cappellacci, L. 5′‑C‑Ethyl-tetrazolyl‑N6‑Substituted Adenosine and 2‑Chloroadenosine Derivatives as Highly Potent Dual Acting A1 Adenosine Receptor Agonists and A3 Adenosine Receptor Antagonists. J. Med. Chem. 2015, 58, 2560-2566.

NOVEL 5'-C-ETHYL-TETRAZOLYL-N6-SUBSTITUTED-ADENOSINE DERIVATIVES: SYNTHESIS AND BIOLOGICAL EVALUATION

SCORTICHINI, MIRKO;CAPPELLACCI, Loredana
2016-01-01

Abstract

Adenosine is an endogenous purine ribonucleoside implicated in the control of the function of many tissues and organs. It exerts a protective action throughout all organs of the body and plays an important role not only in the pathophysiological processes, but also in the modulation of normal processes. Adenosine exerts its effects by interacting with specific G-protein coupled receptors, classified in 4 subtypes: A1, A2A, A2B and A3 (1). A1 adenosine receptor (A1AR) is widely distributed throughout the brain but also in the heart, aorta, liver kidney, bladder and eye. A1AR agonists have shown neuro- and cardioprotective effects, but their clinical use is hampered by severe cardiovascular side effects. A3AR are expressed in multiple organs and at low levels in the CNS. A3AR agonists are in clinical trials for the treatment of cancer and inflammatory diseases, and recent preclinical studies reported their analgesic effects in chronic neuropathic pain (2). Our previous work showed that potent dual A1AR agonists and A3AR antagonists have been obtained combining a 5'-C-ethyl-tetrazolyl moiety and an appropriate N6-substitution in adenosine derivatives (3). A dual A1 agonist and A3 antagonist might be useful in the treatment of glaucoma and other diseases, and might have advantages respect to the combination of two drugs. In order to study the influence of N6-substitution on affinity and selectivity at ARs, a novel series of 5'-C-2-ethyl-tetrazolyl-N6-substituted adenosine derivatives were synthesized and assayed at all human adenosine receptor subtypes. The results of this study will be discussed. (1) Fredholm, B.B.; Ijzerman, A.P.; Jacobson, K:A., Linden, J.; Muller, C.E. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and calssification of adenosine receptors - an update. Pharmacol. Rev. 2011, 63, 1-34. (2) Little, J.W.; Ford, A.; Symons-Liguori, A.M.; Chen, Z.; Janes, K.; Doyle, T.; Xie, J.; Luongo,, L.; Tosh, D.K.; Maione, S.; Bannister, K.; Dickenson, A.; Vandrah, T.W.; Porreca, F.; Jacobson, K.A.; Salvemini, D. Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 2015, 138, 28-35 (3) Petrelli, R.; Torquati, I.; Kachler, S.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Lavecchia, A.; Klotz, K.-N-; Cappellacci, L. 5′‑C‑Ethyl-tetrazolyl‑N6‑Substituted Adenosine and 2‑Chloroadenosine Derivatives as Highly Potent Dual Acting A1 Adenosine Receptor Agonists and A3 Adenosine Receptor Antagonists. J. Med. Chem. 2015, 58, 2560-2566.
2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/391600
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