RO-3 is a potent, CNS-penetrant, and orally active P2X3 and P2X2/3 antagonist with pIC50s of 5.9 and 7.0 for human homomultimeric P2X3 and heteromultimeric P2X2/3 receptors, respectively. RO-3 shows selectivity for P2X3 and P2X2/3 over all other functional homomultimeric P2X receptors (IC50 >10?μM at P2X1,2,4,5,7).IC50 & Target: pIC50: 5.9 (human homomultimeric P2X3 receptor); 7.0 (human heteromultimeric P2X2/3 receptor)In Vivo: In a guinea pig ureter-afferent nerve preparation, and mouse bladder-pelvic nerve preparation, RO-3 dose-dependently reduces afferent nerve activity induced by distension or α,β-meATP.
RO-3 has activity in several rodent models of pain, as well as in cystometry models optimized to measure various parameters associated with sensory regulation of the micturition reflex.
RO-3 has moderate to high metabolic stability in rat and human hepatocytes and liver microsomes, and is highly permeable, orally bioavailable (14%), and has a reasonable in vivo plasma half-life (t1/2=0.41?h) in rats.