PSFL2915

PSFL2915 is an orally active P2X receptor inhibitor, with an IC50 of 0.319 μM for human P2X3, 0.261 μM for rat P2X2/3, and 13.3 μM for human P2X2, demonstrating approximately 42 times selectivity for human P2X3 over human P2X2. It inhibits human P2X3 activation by allosterically tightening the pocket within the head domain needed for channel opening, and this inhibition is magnesium-dependent. PSFL2915 can be utilized in research related to chronic cough.

PSFL2915 (0.01-3 μM; 0.6 μM; 1 μM) is a non-competitive, Mg2+-dependent allosteric inhibitor of hP2X3, with a selectivity for hP2X3 approximately 42 times greater than for hP2X2. It effectively suppresses rP2X2/3 heterotrimers and shows low activity against other P2X subtypes. At a concentration of 1 μM, PSFL2915 inhibits by targeting the internal pocket of the head domain of hP2X3, which is demonstrated by its potent inhibition of hP2X4 chimeras containing this domain. At 500 nM, PSFL2915 can inhibit the ATP-induced conformational change within the internal pocket of the hP2X3 head domain, a change that is crucial for channel activation.

PSFL2915, administered at 15 mg/kg via gavage twice daily for 7 consecutive days, demonstrates significant antitussive activity in male C57BL/6 mice with ammonia-induced chronic cough, showing efficacy comparable to the same dosage of Gefapixant. In male Hartley guinea pigs with chronic cough induced by citric acid/ATP, PSFL2915 at 10 mg/kg administered in the same manner exhibits notable antitussive effects, matching the efficacy of Gefapixant at equivalent doses. Additionally, PSFL2915 at 15 mg/kg given twice daily for 7 to 10 days does not impair taste perception in male C57BL/6 mice, as evidenced by a two-bottle preference test with bitter and sweet substances. Similarly, PSFL2915 at doses ranging from 10 to 20 mg/kg administered intraperitoneally does not affect bitter taste perception in male Sprague Dawley rats, confirmed through a quinine-based two-bottle preference test.