Triazolotriazine A3 adenosine receptor antagonists show neuroprotection in ischemia model
- A set of 2,5,7-trisubstituted triazolo-triazines was built by swapping the C2 furyl group for phenyl or 4-methoxyphenyl, with varied amino groups at C5 and C7.
- A C5 benzylamino group gave sub-nanomolar A3 affinity (compound 15), while the C2 4-methoxyphenyl group drove subtype selectivity of very high (compound 30).
- Docking into the newly solved antagonist-bound A3 receptor structure explained these trends and highlighted residues governing A3 preference.
- In rat hippocampal slices under oxygen-glucose deprivation, compound 15 delayed anoxic depolarization, and given during ischemia it largely prevented it and restored synaptic transmission almost fully.
💡 Points
Separable levers are what a med chemist hopes for: the C5 amine moves affinity and the C2 aryl moves subtype selectivity, so each can be tuned on its own. The catch is that the tightest binder and the most selective compound are different molecules. Until they are merged, and someone reports solubility and brain exposure for this flat polyaromatic core, I would hold the slice data at arm's length.