Sipagladenant (Compound I) is an orally active inverse agonist of the adenosine receptor A2A [1], with potential applications in research on frontal lobe dysfunction [2].

Sipagladenant administered orally at a dosage of 0.3 mg/kg significantly improves cognitive impairment associated with reduced dopamine function in the medial prefrontal cortex, evident through enhanced exploratory behavior towards novel objects (65.03% exploration time) in comparison to familiar ones (34.97%) [2]. Similarly, at a lower dosage of 0.1 mg/kg, Sipagladenant demonstrates an ability to enhance cognitive function, as shown by a notable increase in alternation behavior in ICR mice with cognitive impairment and/or movement disorder [2]. Moreover, this lower dosage also leads to significant improvements in gait parameters, including a larger maximum contact area and gait area of the left hindpaw compared to controls, alongside a tendency for increased contact and gait area in the right forepaw, highlighting its potential in ameliorating mobility-related symptoms [2]. These findings are based on studies conducted in medial prefrontal dopaminergic terminal-lesioned CD(SD) IGS male rats and ICR mice models, indicating Sipagladenant's broad therapeutic potential across different animal models of neurological impairment.