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Ischemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A2A and A1 receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A2A/A1 adenosine receptor (AR)-targeting therapeutic compounds could be a strategy for the treatment of ischemic stroke. Inspired by two clinical phase III drugs, ASP-5854 (dual A2A/A1 AR antagonist) and preladenant (selective A2A AR antagonist), and using the hybrid medici