This study investigates the main protein-ligand interactions between human adenosine receptor subtype A2A (hA2Ar) and caissarone, caffeine, besides other hA2Ar ligands. In the central nervous system (CNS), hA2Ar is highly expressed in basal ganglia. The receptor is activated by adenosine, a negative modulator of dopaminergic signaling, involved in sleep regulation and memory retention; hA2Ar is up-regulated by adenosine in CNS complications. Conversely, hA2Ar can be inhibited by antagonists that block the basal ganglia indirect pathway, increasing dopaminergic signaling and resulting in wakefulness and improved memory. Certain molecules are hA2Ar inhibitors, such as caffeine, and have been studied against some neurological diseases due to neuroprotective properties. Other compounds have also been explored, namely, caissarone, found in Bunodossoma caissarum. Therefore, comparisons among caissarone and other hA2Ar ligands were performed in this work to understand their binding characteristics and evaluate the biological potential of caissarone comparatively to more known compounds (Figure 1). For this, docking simulations using GOLD and calculation of ADMET properties for these molecules were carried out. All the molecules under study shared some superposition on the binding site of the studied target, particularly caffeine and caissarone. Moreover, caissarone seems to be similar to caffeine regarding blood-brain barrier (BBB) permeability and interactions with hA2Ar. Although caissarone shares structural similarities with caffeine, it might demand structural optimization and/or a specific formulation to enhance desirable attributes and minimize toxicity risks, so that it can be further explored in future studies.