A brain penetrant EP2 antagonist
IC50: 2.4 nM for KB EP2; 11.4 nM for KB EP4
TG4-155 is a brain penetrant EP2 antagonist.
Prostaglandin E2 (PGE2) evokes distinct responses via four different ‘E prostanoid’ (EP) receptors. EP2, a G protein-coupled receptor, has diverse roles, such as those in cancer, inflammation, and neuroprotection.
In vitro: Using a set of cell-based TR-FRET assays of cAMP formation, a previous study screened a small molecule library and identified TG4-155 and TG4-166 as the most potent ones. TG4-155 and TG4-166 also showed robust inhibition of PGE2 -induced cAMP accumulation in human EP2-overexpressing C6 glioma cells, without affecting prostaglandin EP4 or β2-adrenergic receptors. Both TG4-155 and TG4-166 could cause a robust rightward shift in the PGE2 dose–response curve without affecting the maximal response to PGE2. TG4-155 at 1 μM caused 1,120-fold shift and TG4-166 at 1 μM caused a 651-fold shift in the PGE2 EC50 [1].
In vivo: TG4-155 could significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of TG4-155 raised the possibility that selective block of EP2 signaling through small molecules can be an innovative therapeutic strategy for inflammation-related brain injury [1].
Clinical trial: So far, no clinical study has been conducted.
Reference:
[1] Jiang, J.?,Ganesh, T.,Du, Y., et al. Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2. Proceedings of the National Academy of Sciences of the United States of America 109(8), 3149-3154 (2012).
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