Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

Abstract

Truncated N6-substituted-4′-oxo- and 4′-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A2A and A3 adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA2AAR, but hydrophobic C8 substitution abolished binding at the hA2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA3AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA2AAR agonists. C2 substitution probed geometrically through hA2AAR-docking, was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA2AAR agonist and hA3AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.

The role of experimental and computational structural approaches in 7TM drug discovery

“…The homology models explained binding modes and subtype selectivity among these receptors for a diverse set of AR antagonists. Other very effective homology models were used to rationalize agonist activities at the serotonin 5HT 1A receptor [95] and the somatostatin receptor subtype 4 [39], the activity of nucleosides at the A1 and A3 receptors [96,97], and inverse agonism/antagonism versus partial/full agonism activities of b 2 AR ligands [98,99]. Constructed from the dopamine D3 receptor X-ray structure as a template, D3R and D2R homology models were refined by molecular dynamics to guide in the design of highly D3R-selective ligands with desired efficacies [100].…”

New selective A2Aagonists and A3antagonists for human adenosine receptors: synthesis, biological activity and molecular docking studies

“…blockage, it had no significant effect on rhinorrhoea, number of sneezes or peak nasal inspiratory flow measurements when compared with placebo. 21 The most potent compound found, the 2-hexynyl derivative, resulted to be a potent antiinflammatory agent on carrageenan-induced paw edema in rats, with the effect being similar to that of indomethacin. 27 More recently and in the same context, N6-substituted-4′-thioadenosine derivatives have resulted to be potent ligands as A 2A AR agonists and A 3 AR antagonists.…”

“…1C and D, respectively. 20,21 The efficacy of adenosine derivatives on the A 3 AR might contrast with that found in the other receptor subtypes, and thus, agonists in the A 1 AR were described as A 3 antagonists. Only compounds (S)-6 and 10 showed lower E max than NECA, and therefore, they can be considered as partial agonists.…”

“…26 The ligand was also able to inhibit the generation of reactive oxygen species from human eosinophils and the release of preformed granule proteins from neutrophils and eosinophils in human blood. 21 To gain further insight into the structure-affinity relationships, we undertook a docking study of our compound series on the A 2A AR. 21 The most potent compound found, the 2-hexynyl derivative, resulted to be a potent antiinflammatory agent on carrageenan-induced paw edema in rats, with the effect being similar to that of indomethacin.…”

Exploring the Role of N6-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

“…5 Hou et al reported dual acting hA 2A agonists and hA 3 AR antagonists potentially useful in asthma and inflammatory diseases. 6 …”