MRS4596 is a Potent and Selective P2X4 Receptor Antagonist

P2X4 receptor is a member of P2X receptors. P2X receptors are widely expressed in different tissues and plays different roles in various disease regulatory pathways. Among them, P2X4 receptor is one of the most sensitive purinergic receptors and it expresses in central and peripheral neurons and various epithelial and endothelial cells. Moreover, The upregulation of P2X4 receptor activates p39 mitogen-activated protein kinases, which are related to neuropathic pain. This result in the release of brain-derived neurotrophic factor (BDNF) from microglia. When the released BDNF interacts with the TrkB receptor thereupon induces neuronal hyperexcitability. So far, P2X4 receptor has become a potential therapeutic target in multiple pathologies, such as rheumatoid arthritis, neurodegenerative diseases, and chronic pain. Therefore, as an important target for many diseases, P2X4 receptor has attracted extensive attention. Here, we will introduce a potent and selective P2X4 receptor antagonist, MRS4596.

MRS4596 is a potent and selective P2X4 receptor antagonist with neuroprotective.

From: Stokes L, Fountain SJ, et al. Front Pharmacol. 2017 May 23;8:291.

MRS4596 is an analogue of 1,5-Dihydro‑2H‑naphtho[1,2‑b][1,4]diazepine-2,4(3H)‑dione which is a known P2X4 receptor-selective antagonist with excellent in vitro and in vivo activities. It is an active compound based on the extensive modification of 1,5-Dihydro‑2H‑naphtho[1,2‑b][1,4]diazepine-2,4(3H)‑dione.

According to the experiment results in vitro, this antagonist shows an inhibitory effect on the human P2X4 receptors. MRS4596 inhibits the P2X4 receptor with an IC50 value of 1.38 μM. Besides, in vivo, MRS4596 (5 mg/kg, 3 days continuous infusion) exhibits neuroprotective, and learning- and memory-enhancing effects. Additionally, MRS4596 decreases the total hemispheric infarct volume in mouse middle cerebral artery occlusion (MCAO) models.

In conclusion, MRS4596 is a potent and selective P2X4 receptor antagonist with neuroprotective effects, and has great potential to research neurodegenerative diseases and hypomnesis.