Description
Prostaglandin E
2 (PGE
2) evokes distinct responses through four different ‘E prostanoid’ (EP) receptors. EP
2 is a G protein-coupled receptor that has diverse roles, including those in cancer, inflammation, and neuroprotection. TG4-155 is a brain penetrant EP
2 antagonist (K
B = 2.4 nM) that is over 1000-fold less effective at EP
4 (K
B = 11.4 μM) and a panel of other receptors and channels. It blocks the induced expression of inflammatory markers in microglial cells treated with the selective EP
2 agonist butaprost alone or with LPS and IFNγ. TG4-155 significantly reduces neurodegeneration in a mouse model of status epilepticus, induced by pilocarpine . It inhibits proliferation, invasion, and inflammatory cytokine expression in cancer cells treated with butaprost.
Uses
TG4-155 is a pharmacological agent which reduces neurodegeneration in a mouse model status of epilepticus induced by pilocarpine. Inhibits proliferation, inflammatory cytokine expression in cancer cells.
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].
IC 50
2.4 nm for kb ep2; 11.4 nm for kb ep4
References
1) Jiang and Dingledine (2013),?Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation; J. Pharmacol. Exp. Ther.?344?360
2) Quan?et al.?(2013),?EP2 Receptor Signaling Pathways Regulate Classical Activation of Microglia; J. Biol. Chem.?288?9293
