Adenosine receptors (ARs) belong to the G protein-coupled receptor (GPCR) family, and can be subdivided into four subtypes A1, A2A, A2B and A3. A1 and A3 receptor subtypes couple to Gi-proteins, mediating the inhibition of adenylyl cyclase and a decrease in cAMP levels, whereas A2A and A2B receptors activate adenylyl cyclase and increase cAMP levels via the stimulatory Gs-proteins [1]. In the last two decades many selective ligands for a certain AR subtype have been developed and some are in clinical use. More recently the concept of multitarget drugs has emerged as strategy to potentiate efficacy (either additively or synergistically) and/or to reduce side effects. The dual-acting ligands of ARs may have considerable promise as novel approaches to treat pathological conditions e.g. ischemic conditions, asthma, inflammatory diseases and glaucoma. Our recent work discovered the first dual A1AR agonists and A3AR antagonists [2] by combining a 5’-C-ethyl-tetrazolyl moiety and an appropriate N6-substitution in adenosine derivatives. In order to better understand the role of the substituent in N6 position, a series of novel 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] B.B. Fredholm, A.P. IJzerman, K.A. Jacobson, J. Linden and C. Muller Pharmacol. Rev. 63 (2011) 1−34. [2] R. Petrelli, I. Torquati, S. Kachler, L. Luongo, S. Maione, P. Franchetti, M. Grifantini, E. Novellino, A. Lavecchia, K.-N. Klotz and L. Cappellacci J. Med. Chem. 58 (2015) 2560-2566.
Synthesis and biological evaluation of novel potent dual acting ribose modified N6-substitued adenosine derivatives
SCORTICHINI, MIRKO;PETRELLI, Riccardo;ANGELONI, YARA;CAPPELLACCI, Loredana
2015-01-01
Abstract
Adenosine receptors (ARs) belong to the G protein-coupled receptor (GPCR) family, and can be subdivided into four subtypes A1, A2A, A2B and A3. A1 and A3 receptor subtypes couple to Gi-proteins, mediating the inhibition of adenylyl cyclase and a decrease in cAMP levels, whereas A2A and A2B receptors activate adenylyl cyclase and increase cAMP levels via the stimulatory Gs-proteins [1]. In the last two decades many selective ligands for a certain AR subtype have been developed and some are in clinical use. More recently the concept of multitarget drugs has emerged as strategy to potentiate efficacy (either additively or synergistically) and/or to reduce side effects. The dual-acting ligands of ARs may have considerable promise as novel approaches to treat pathological conditions e.g. ischemic conditions, asthma, inflammatory diseases and glaucoma. Our recent work discovered the first dual A1AR agonists and A3AR antagonists [2] by combining a 5’-C-ethyl-tetrazolyl moiety and an appropriate N6-substitution in adenosine derivatives. In order to better understand the role of the substituent in N6 position, a series of novel 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] B.B. Fredholm, A.P. IJzerman, K.A. Jacobson, J. Linden and C. Muller Pharmacol. Rev. 63 (2011) 1−34. [2] R. Petrelli, I. Torquati, S. Kachler, L. Luongo, S. Maione, P. Franchetti, M. Grifantini, E. Novellino, A. Lavecchia, K.-N. Klotz and L. Cappellacci J. Med. Chem. 58 (2015) 2560-2566.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
