Adenosine receptors (ARs) are widely distributed throughout the body and are present in basically all cells, making them an interesting target for pharmacologic intervention in many pathophysiologic conditions. ARs belong to the family of G-protein coupled receptors (GPCRs) and are divided in four subtypes: A1, A2A, A2B and A3. A1AR agonists are known to have antiarrhythmic, antinociceptive, anticonvulsant effects and to mediate neuroprotective effects through microglial cells. Moreover, A1AR agonists reduce lipolysis in adipose tissue and reduce elevated intraocular pressure (IOP) in glaucoma. Selectivity for the A1AR may be achieved by substitution of the N6-position of adenosine with a wide range of cycloalkyl-, bicycloalkyl-, and arylalkyl groups. Moreover, modifications at the ribose moiety contributes to A1AR affinity, selectivity, and efficacy, leading to full or partial A1 agonists [1]. Our previous work showed that replacement of the 5′-hydroxy group by a chlorine atom in N6-substituted adenosine derivatives increased selectivity for A1AR [2]. 5′-Chloro-5′-deoxy-N6-(±)-(endo- norborn-2-yl)-adenosine (5′Cl5′d-(±)-ENBA) displayed high A1AR affinity and selectivity. It was shown to reduce both mechanical allodynia and thermal hyperalgesia in a mice model of neuropathic pain without affecting motor and cardiovascular functions [3] and to reduce dyskinesia evoked by L-DOPA in a mice model of Parkinson’ s disease [4]. As part of our interest in identifying potent and selective A1AR agonists, we were interested in novel nucleosides modified in 5’- and N6- positions. In particular, 5’-deoxy-5’-N-pyrazolyl- N6-substituted adenosine derivatives were synthesized and tested in binding assays and in formalin test in mice. Based on our previous results on 5′Cl5′d-(±)-ENBA, we also tested the intermediates for the synthesis of the designed compounds, i.e. the 5’-deoxy-5’-chloro-N6- substituted adenosine derivatives. The results of our biological evaluation will be presented. [1] Cappellacci L, Petrelli R, Klotz K-N et al. Bioorg. Med. Chem. 2008, 16, 336. [2] Franchetti P, Cappellacci L, Petrelli R, Klotz, K-N et al. J. Med. Chem. 2009, 52, 2393. [3] (a) Luongo L, Petrelli R, Cappellacci L, Maione S et al. Molecules 2012, 17, 13712 (b) Luongo L, Petrelli R, Cappellacci L, Maione S. et al. Glia 2014, 62, 122. [4] Mango D, Cappellacci L, Petrelli R, Mercuri NB et al. Exp. Neurol. 2014, 261, 733. This work was supported by the Italian MIUR fund (PRIN2009, prot. no. 200928EEX4_004 to P.R.)

5’-deoxy-5’-N-pyrazolyl-N6-substituded adenosine derivates as A1 adenosine receptor agonists: synthesis and antinociception in mice

PETRELLI, Riccardo;TORQUATI, ILARIA;VITA, PATRIZIA;SCORTICHINI, MIRKO;CAPPELLACCI, Loredana
2015-01-01

Abstract

Adenosine receptors (ARs) are widely distributed throughout the body and are present in basically all cells, making them an interesting target for pharmacologic intervention in many pathophysiologic conditions. ARs belong to the family of G-protein coupled receptors (GPCRs) and are divided in four subtypes: A1, A2A, A2B and A3. A1AR agonists are known to have antiarrhythmic, antinociceptive, anticonvulsant effects and to mediate neuroprotective effects through microglial cells. Moreover, A1AR agonists reduce lipolysis in adipose tissue and reduce elevated intraocular pressure (IOP) in glaucoma. Selectivity for the A1AR may be achieved by substitution of the N6-position of adenosine with a wide range of cycloalkyl-, bicycloalkyl-, and arylalkyl groups. Moreover, modifications at the ribose moiety contributes to A1AR affinity, selectivity, and efficacy, leading to full or partial A1 agonists [1]. Our previous work showed that replacement of the 5′-hydroxy group by a chlorine atom in N6-substituted adenosine derivatives increased selectivity for A1AR [2]. 5′-Chloro-5′-deoxy-N6-(±)-(endo- norborn-2-yl)-adenosine (5′Cl5′d-(±)-ENBA) displayed high A1AR affinity and selectivity. It was shown to reduce both mechanical allodynia and thermal hyperalgesia in a mice model of neuropathic pain without affecting motor and cardiovascular functions [3] and to reduce dyskinesia evoked by L-DOPA in a mice model of Parkinson’ s disease [4]. As part of our interest in identifying potent and selective A1AR agonists, we were interested in novel nucleosides modified in 5’- and N6- positions. In particular, 5’-deoxy-5’-N-pyrazolyl- N6-substituted adenosine derivatives were synthesized and tested in binding assays and in formalin test in mice. Based on our previous results on 5′Cl5′d-(±)-ENBA, we also tested the intermediates for the synthesis of the designed compounds, i.e. the 5’-deoxy-5’-chloro-N6- substituted adenosine derivatives. The results of our biological evaluation will be presented. [1] Cappellacci L, Petrelli R, Klotz K-N et al. Bioorg. Med. Chem. 2008, 16, 336. [2] Franchetti P, Cappellacci L, Petrelli R, Klotz, K-N et al. J. Med. Chem. 2009, 52, 2393. [3] (a) Luongo L, Petrelli R, Cappellacci L, Maione S et al. Molecules 2012, 17, 13712 (b) Luongo L, Petrelli R, Cappellacci L, Maione S. et al. Glia 2014, 62, 122. [4] Mango D, Cappellacci L, Petrelli R, Mercuri NB et al. Exp. Neurol. 2014, 261, 733. This work was supported by the Italian MIUR fund (PRIN2009, prot. no. 200928EEX4_004 to P.R.)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/391498
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