Adenosine receptors (ARs) are members of the G protein-coupled receptors superfamily (GPCRs). They can be subdivided into four subtypes A1, A2A, A2B and A3. Over the past two decades, many synthetic ligands have been developed that selectively bind to a determined receptor subtype along with different functional profiles: partial or full agonists and antagonists. Potent and selective ligands of a certain AR subtype are in advanced clinical trials. Recent findings indicated that some compounds might act through two different subtypes of a receptor family, with both pathways leading to beneficial effects. A dual A2B and A3 AR antagonist was developed by Novartis as an antiasthmatic agent, while GlaxoSmithKline has investigated a dual A2A agonist and A3 antagonist as anti-inflammatory agent. Dual A2A agonists and A3 antagonists that might be advantageous for asthma or other inflammatory diseases, have been also reported [1]. Our recent work discovered the first dual acting A1AR agonists and A3AR antagonists [2] potentially useful in the treatment of some pathological conditions such as glaucoma and epilepsy. We found that the combination of 5’- C-ethyl-tetrazolyl moiety with the appropriate N6-substitution in adenosine derivatives improved affinity for both A1 and A3AR. A methyl- group at the N6 position of the 5′-C-2- ethyl-2H-tetrazolyl-adenosine derivatives was beneficial for high binding affinity at the A3, whereas a cyclopentyl-, endo-(±)-norbornyl- or 2-fluoro-4-chlorobenzyl-group conferred subnanomolar affinity for A1. Unexpectedly, the 5′-C-2-ethyl-2H-tetrazolyl-adenosine and the corresponding 2-chloro-adenosine showed high affinities for A1 and A3 and also for A2A, resulting in potent but non selective ligands. In order to better explore the influence of N6- substitution on AR affinity and selectivity of this class of AR ligands, novel 5’-C-2-ethyl- tetrazolyl-N6-substituted adenosine derivatives were synthesized and assayed at all human adenosine receptor subtypes. The results of these studies will be discussed. [1] Hou X, Majik MS, Kim K, Pyee Y, Lee Y, Alexander V, Chung H-J et al. J. Med. Chem. 2012, 55, 342. [2] Petrelli R, Lavecchia A, Luongo L, Maione S, Klotz KN, Cappellacci L et al J. Med. Chem. 2015, 58, 2560. This work was supported by the Italian MIUR fund (PRIN2009, prot. no. 200928EEX4_004 to P.R.).

Novel dual acting 5’-C-ethyl-tetrazolyl-N6-substituted adenosine derivatives: synthesis and biological evaluation

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

Abstract

Adenosine receptors (ARs) are members of the G protein-coupled receptors superfamily (GPCRs). They can be subdivided into four subtypes A1, A2A, A2B and A3. Over the past two decades, many synthetic ligands have been developed that selectively bind to a determined receptor subtype along with different functional profiles: partial or full agonists and antagonists. Potent and selective ligands of a certain AR subtype are in advanced clinical trials. Recent findings indicated that some compounds might act through two different subtypes of a receptor family, with both pathways leading to beneficial effects. A dual A2B and A3 AR antagonist was developed by Novartis as an antiasthmatic agent, while GlaxoSmithKline has investigated a dual A2A agonist and A3 antagonist as anti-inflammatory agent. Dual A2A agonists and A3 antagonists that might be advantageous for asthma or other inflammatory diseases, have been also reported [1]. Our recent work discovered the first dual acting A1AR agonists and A3AR antagonists [2] potentially useful in the treatment of some pathological conditions such as glaucoma and epilepsy. We found that the combination of 5’- C-ethyl-tetrazolyl moiety with the appropriate N6-substitution in adenosine derivatives improved affinity for both A1 and A3AR. A methyl- group at the N6 position of the 5′-C-2- ethyl-2H-tetrazolyl-adenosine derivatives was beneficial for high binding affinity at the A3, whereas a cyclopentyl-, endo-(±)-norbornyl- or 2-fluoro-4-chlorobenzyl-group conferred subnanomolar affinity for A1. Unexpectedly, the 5′-C-2-ethyl-2H-tetrazolyl-adenosine and the corresponding 2-chloro-adenosine showed high affinities for A1 and A3 and also for A2A, resulting in potent but non selective ligands. In order to better explore the influence of N6- substitution on AR affinity and selectivity of this class of AR ligands, novel 5’-C-2-ethyl- tetrazolyl-N6-substituted adenosine derivatives were synthesized and assayed at all human adenosine receptor subtypes. The results of these studies will be discussed. [1] Hou X, Majik MS, Kim K, Pyee Y, Lee Y, Alexander V, Chung H-J et al. J. Med. Chem. 2012, 55, 342. [2] Petrelli R, Lavecchia A, Luongo L, Maione S, Klotz KN, Cappellacci L et al J. Med. Chem. 2015, 58, 2560. This work was supported by the Italian MIUR fund (PRIN2009, prot. no. 200928EEX4_004 to P.R.).
2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/391499
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