Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A 3 and A 2A subtypes.

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.
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