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Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A3 and A2A subtypes

By Daniela Poli, Matteo Falsini, Flavia Varano, Marco Betti, Katia Varani, Fabrizio Vincenzi, Anna Maria Pugliese, Felicita Pedata, Diego Dal Ben, Ajiroghene Thomas, Ilaria Palchetti, Francesca Bettazzi, Daniela Catarzi and Vittoria Colotta


The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A3 or the hA2A receptor subtype. The N8-(hetero)arylcarboxyamido substituted compounds 4–14 and 21–30, bearing a 6-phenyl moiety or not, respectively, show good hA3 receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA2A receptor subtype (compounds 31–38) and also the 6-phenyl analogues 18–20 do not bind the hA2A AR, or show hA1 or balanced hA1/hA2A AR affinity in the micromolar range. Molecular docking of the new hA3 antagonists was carried out to depict their hypothetical binding mode to our refined model of the hA3 receptor. Some derivatives were evaluated for their fluorescent potentiality and showed some fluorescent emission properties. One of the most active hA3 antagonists herein reported, i.e. the 2,6-diphenyl-8-(3-pyridoylamino)imidazo[1,2-a]pyrazine 29, tested in a rat model of cerebral ischemia, delayed the occurrence of anoxic depolarization caused by oxygen and glucose deprivation in the hippocampus and allowed disrupted synaptic activity to recover

Topics: Adenosine receptor antagonists, Bicyclic heteroaromatic systems, G protein-coupled receptors, Imidazopyrazines, Ligand-receptor modeling studies, Pharmacology, Drug Discovery3003 Pharmaceutical Science, Organic Chemistry
Year: 2017
DOI identifier: 10.1016/j.ejmech.2016.09.076
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