A selective EP4 receptor antagonist
Ki: 3.16 nM: antagonizes E prostanoid receptor 4 (EP4).
Ki: 631 nM: antagonizes EP2.
CJ-42794, as a selective antagonist of EP4, less binds to EP2 and does not have binding affinity for EP1 or EP3. It displays minimal effect on numerous other receptors, channels, or enzymes. CJ-42794 delays the healing of gastric ulcers, inhibiting the upregulation of VEGF expression and angiogenesis. EP4, activated by prostaglandin E2 (PGE2), is a G-protein-coupled receptor, which plays vital roles in bone formation and resorption, cancer, and atherosclerosis via elevating the second messenger cyclic AMP (cAMP).
In vitro: CJ-42794 exhibited remarkable binding activity to EP4 and suppressed PGE2-triggered elevations of intracellular cAMP levels in a concentration-dependent fashion in HEK293 cells overexpressing human EP4. Moreover, CJ-42794, concentration-dependently, reversed the inhibitory effects of PGE2 on lipopolysaccharide-evoked tumor necrosis factor α production, which suggested that CJ-42794 had excellent pharmacological properties used for exploring the physiological role of EP4 [1].
In vivo: Male Sprague-Dawley rats and C57BL/6 mice were given subcutaneously 3 and 10 mg/kg for rats, 10 mg/kg for mice once daily for 7 or 14 days. Compared to the controls, CJ-42794, in a dose-dependent manner, impaired and delayed the gastric ulcer healing in rats and mice. CJ-42794 markedly dampened the increase of VEGF expression in ulcerated mucosa of the mouse stomach and the primary gastric fibroblasts of rat [2].
参考文献:
[1].? Murase, A., Taniguchi, Y., Tonai-Kachi, H., Nakao, K., & Takada, J. In vitro pharmacological characterization of CJ-042794, a novel, potent, and selective prostaglandin EP4 receptor antagonist. Life Sciences. 2008; 82(3-4): 226-232.
[2].? Hatazawa, R., Tanaka, A., Tanigami, M., Amagase, K., Kato, S., Ashida, Y., & Takeuchi, K. Cyclooxygenase-2/prostaglandin E2 accelerates the healing of gastric ulcers via EP4 receptors. AJP: Gastrointestinal and Liver Physiology. 2007; 293(4): G788-G797.
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