Denufosol

Denufosol is a long- acting P2Y₂ receptor agonist, which exhibits an EC₅₀ of ~10 μM for P2Y₂ receptor activation. IC50 & Target: EC50: 10 μM (P2Y₂ receptor)^[1] In Vitro: Denufosol can be maintained above the EC₅₀ point for 6 to 8 hours on the airway surface of airway cultures. Denufosol produces a significant increase in airway surface layer (ASL) height, reflecting P2Y₂ receptor–mediated fluid secretion, which is terminated rapidly, likely reflecting P2Y₂ receptor desensitization. The secreted ASL is reabsorbed over time, despite the continued presence of Denufosol at values exceeding its EC₅₀, albeit at a rate slower than without Denufosol exposure (compared to vehicle group). This latter finding is consistent with the observation that P2Y₂ receptor–mediated inhibition of Na⁺ absorption may persist for larger intervals than P2Y₂ receptor activation of Cl^- secretion^[1]. Denufosol is a deoxycytidine-uridine dinucleotide with agonist activity at the P2Y₂ receptor. In a concentration-dependent manner, Denufosol induces the mobilization of intracellular calcium in 1321N1 astrocytoma cells stably expressing human P2Y₂ and P2Y₄ receptors with EC₅₀s of 0.22 and 0.8 μM, respectively. The efficacy of Denufosol is identical to that of UTP, indicating that Denufosol is a full agonist of P2Y₂ and P2Y₄ receptors. Denufosol is a weak agonist of P2Y₆ receptors in which 100 μM Denufosol produces approximately 70% of the response observed with the natural agonist UDP^[2]. In Vivo: The P2Y₂ receptor agonist Denufosol improves the rate of retinal reattachment in animal models of induced Retinal detachment (RD), and has been shown to also significantly enhance the rate of ERG recovery in a mouse model of RD. The identification of genes modulated by Denufosol may allow further drug discovery for treating RD and edema. RD is induced in Balb/cJ mice by transvitreal subretinal injections of 1 μL saline or of 1 μL of 10 μM Denufosol/saline to cause detachment and to expedite the rate of recovery^[3].