Pyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one as a New Scaffold To Develop Potent and Selective Human A3 Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluation, and Ligand-Receptor Modeling Studies.

The paper describes a new class of human (h) A3 adenosine receptor antagonists, the 2-arylpyrido[2,3-e]- 1,2,4-triazolo[4,3-a]pyrazin-1-one derivatives (PTP), either 4-oxo (1-6, series A) or 4-amino-substituted (7-20, series B). In both series A and B, substituents able to act as hydrogen bond acceptors (OMe, OH, F, COOEt) were inserted on the 2-phenyl ring. In series B, cycloalkyl and acyl residues were introduced on the 4-amino group. Some of the new derivatives showed high hA3 AR affinities (Ki < 50 nM) and selectivities vs both hA1 and hA2A receptors. The selected 4-benzoylamino-2-(4-methoxyphenyl)pyrido[2,3-e]-1,2,4- triazolo[4,3-a]pyrazin-1-one (18), tested in an in vitro rat model of cerebral ischemia, proved to be effective in preventing the failure of synaptic activity induced by oxygen and glucose deprivation in the hippocampus. Molecular docking of this new class of hA3 AR antagonists was carried out to depict their hypothetical binding mode to our refined model of hA3 receptor.