P2X Antagonist III

A phenylthio-nicotinamide that acts as a high affinity P2X₇ antagonist (pK_i = 8.7 and 7.9, respectively, against 30 nM A-804598 for rat and human P2X₇ binding) and potently inhibits P2X₇-dependent cellular Ca²⁺ mobilization (pIC₅₀ = 8.3, 7.5, and 7.2, respectively, using 1321N1 expressing human, mouse, or rat P2X₇; drug added 0.5 h prior to 3 min 0.25 mM BzATP stimulation) and IL-1β secretion (pIC₅₀ = 7.6; drug added 0.5 h prior to 1.5 h 0.5 mM BzATP stimulation of LPS-activated human PBMC), while exhibiting much reduced or little potency toward a panel of 50 ion channels, transporters, and receptors (pIC₅₀<6). Although not suitable for oral dosing due to high hepatic extraction ratios (>0.92 in human, mouse, and rat), effective delivery (t_max = 15 min & C_max ~8.5 µg/mL in plasma and brain; 30 mg/kg s.c.) and brain P2X₇ occupancy (>50% and >80% at t_max following s.c. dose of 3.2 mg/kg and 32 mg/kg, respectively) can be achieved via s.c. dosing in rats in vivo.

Cell permeable: yes

Primary Target
P2X₇

Reversible: yes

Packaged under inert gas

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Use only fresh DMSO for reconstitution.

Letavic, M. A., et al. 2013. Br. J. Pharmacol.4, 419.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)