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

Abstract 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) A 3 or the hA 2A receptor subtype. The N 8 -(hetero)arylcarboxyamido substituted compounds 4–14 and 21–30 , bearing a 6-phenyl moiety or not, respectively, show good hA 3 receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA 2A receptor subtype (compounds 31–38 ) and also the 6-phenyl analogues 18–20 do not bind the hA 2A AR, or show hA 1 or balanced hA 1 /hA 2A AR affinity in the micromolar range. Molecular docking of the new hA 3 antagonists was carried out to depict their hypothetical binding mode to our refined model of the hA 3 receptor. Some derivatives were evaluated for their fluorescent potentiality and showed some fluorescent emission properties. One of the most active hA 3 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.