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

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. (C) 2016 Elsevier Masson SAS. All rights reserved.