In the last 20 years intense medicinal chemical efforts led to the synthesis of a variety of adenosine receptor (AR) agonists and antagonists for the pharmacological characterization of this family of G protein-coupled receptors.1 Several classes of heterocyclic derivatives have been reported as AR antagonists with high levels of both affinity and selectivity. Recently, the synthesis of more simplified heterocyclic derivatives has been strongly investigated in order to obtain derivatives with a better pharmacokinetic profile. In particular bicyclic systems such as adenine, triazolo-pyrazine, triazolo-pyrimidines and triazolo-triazine could be considered some of the most promising targets.2 One of the most appealing bicyclic core is the triazolo-triazine nucleus, which led in the past to the discovery of potent and selective A2A AR antagonists, such as ZM241385.3 In the past, our group performed a study on this nucleus trying to optimize substitution at the C5 and N7 positions with the aim of improving affinity and selectivity versus the hA2BAR and hA3AR subtypes. In particular, inclusion at the N7 position of arylcarbamoyl (for A3) or arylacetyl (for A2B) moieties, which gave good results in the pyrazolotriazolopyrimidine family, has been investigated.4 Unfortunately, none of these substitutions led to the desired selectivity. Regarding the A3 subtype, lack of affinity was probably observed because only lipophilic moieties were present at the 5 position (phenoxy, dimethylamino, thiomethyl) avoiding the formation of hydrogen bonds with residues inside the binding pocket of the A3 adenosine receptor. Our aim, in this work, was to synthesise new [1,2,4]triazolo[1,5-a][1,3,5]triazines introducing substituents at the 5 position able to form hydrogen bonds, such as monosubstituted amines, in order to verify if it is capable of enhance affinity and selectivity towards the A3 AR. The analogues were docked in a homology model of the hA3 AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed in order to support the experimental binding data.References (1) Moro, S, et al. Med. Res. Rev. 2006, 26, 131-159. (2) Muller, C, et al. Biochim. Biophys. Acta 2010, 1808, 1290-1308. (3) Poucher, SM, et al. Br. J. Pharmacol. 1995, 115, 1096–1102. (4) Pastorin, G, et al. Bioorg. Med. Chem. 2010, 18, 2524-2536.

[1,2,4]Triazolo[1,5-a][1,3,5]Triazine Derivatives as Antagonists for the Adenosine Receptors: a Preliminary Study on Affinity at the A3 Subtype

FEDERICO, STEPHANIE;MORO, STEFANO;SPALLUTO, GIAMPIERO
2013

Abstract

In the last 20 years intense medicinal chemical efforts led to the synthesis of a variety of adenosine receptor (AR) agonists and antagonists for the pharmacological characterization of this family of G protein-coupled receptors.1 Several classes of heterocyclic derivatives have been reported as AR antagonists with high levels of both affinity and selectivity. Recently, the synthesis of more simplified heterocyclic derivatives has been strongly investigated in order to obtain derivatives with a better pharmacokinetic profile. In particular bicyclic systems such as adenine, triazolo-pyrazine, triazolo-pyrimidines and triazolo-triazine could be considered some of the most promising targets.2 One of the most appealing bicyclic core is the triazolo-triazine nucleus, which led in the past to the discovery of potent and selective A2A AR antagonists, such as ZM241385.3 In the past, our group performed a study on this nucleus trying to optimize substitution at the C5 and N7 positions with the aim of improving affinity and selectivity versus the hA2BAR and hA3AR subtypes. In particular, inclusion at the N7 position of arylcarbamoyl (for A3) or arylacetyl (for A2B) moieties, which gave good results in the pyrazolotriazolopyrimidine family, has been investigated.4 Unfortunately, none of these substitutions led to the desired selectivity. Regarding the A3 subtype, lack of affinity was probably observed because only lipophilic moieties were present at the 5 position (phenoxy, dimethylamino, thiomethyl) avoiding the formation of hydrogen bonds with residues inside the binding pocket of the A3 adenosine receptor. Our aim, in this work, was to synthesise new [1,2,4]triazolo[1,5-a][1,3,5]triazines introducing substituents at the 5 position able to form hydrogen bonds, such as monosubstituted amines, in order to verify if it is capable of enhance affinity and selectivity towards the A3 AR. The analogues were docked in a homology model of the hA3 AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed in order to support the experimental binding data.References (1) Moro, S, et al. Med. Res. Rev. 2006, 26, 131-159. (2) Muller, C, et al. Biochim. Biophys. Acta 2010, 1808, 1290-1308. (3) Poucher, SM, et al. Br. J. Pharmacol. 1995, 115, 1096–1102. (4) Pastorin, G, et al. Bioorg. Med. Chem. 2010, 18, 2524-2536.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2834216
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