Background: A₃AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A₃AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A₃AR antagonists by the exploration of novel diversity spaces is a challenging goal. Results: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A₃AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure–activity and structure–selectivity relationships in this series. Conclusion: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.