P2X3 antagonist 34, a potent, selective, and orally active antagonist, targets the P2X3 homotrimeric receptor, exhibiting IC50s of 25 nM, 92 nM, and 126 nM for human, rat, and guinea pig P2X3 receptors respectively. It shows reduced activity against P2X2/3 heterotrimeric receptors across human, rat, and guinea pig models. Notably, this compound demonstrates a significant anti-tussive effect without altering taste[1].

P2X2/3 heterotrimeric receptor (guinea pig):3450 nM , P2X3 receptor (rat):92 nM , P2X2/3 heterotrimeric receptor (rat):1820 nM , P2X3 receptor (human):25 nM

P2X3 antagonist 34 (BLU-5937; 500 nM) can block αβ-meATP-induced sensitization and firing activity of isolated primary nociceptors in rat dorsal root ganglions (DRGs), through P2X3 homotrimeric receptor antagonism. The sensitizing effect of αβ-meATP and the inhibition of P2X3 antagonist 34 are reversible after washout [1].

P2X3 antagonist 34 (BLU-5937; 0.3-0 mg/kg, oral administration; male Dunkin Hartley guinea pigs) treatment significantly reduces the histamine-induced enhancement in the number of citric acid-induced coughs in a dose-dependent manner in a guinea pig cough model [1]. P2X3 antagonist 34 (BLU-5937; 3 and 30 mg/kg, oral) is also shown to reduce significantly and dose-dependently the ATP-induced enhancement of citric acid-induced coughs in the guinea pig [1]. Animal Model: Male Dunkin Hartley guinea pigs [1] Dosage: 0.3 mg/kg, 3 mg/kg, 30 mg/kg Administration: Oral administration Result: Significantly reduced the histamine-induced enhancement in the number of citric acid-induced coughs in a dose-dependent fashion.