PSB-12054 is a P2X4 receptor antagonist with IC50 values of 0.19 μM, 2.10 μM and 1.77 μM against human, rat and mouse receptors, respectively, and exhibits selectivity over other human P2X receptor subtypes. PSB-12054 inhibits ATP-induced calcium influx, suppresses shear stress-induced transverse Ca 2+ wave generation, and elevates basal Ca 2+ levels in rat atrial myocytes. PSB-12054 binds to the 5-HT2B receptor. PSB-12054 can be used in research related to neuropathic pain, traumatic brain injury, cerebral ischemia and spinal cord injury [1] [2] [3] [4].
In Vivo, PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs HSPC homing by 40%, early engraftment by more than 50%, and delays peripheral blood cell recovery in lethally irradiated mice[4]. PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs G-CSF-induced HSPC mobilization in wild-type mice[4]. PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs short-term AMD3100-induced HSPC mobilization in wild-type mice[4]. PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs AMD3100 (Plerixafor) -induced HSPC mobilization in P2X7-KO mice[4].
In Vitro, PSB-12054 (10 μM; 4-5 min) suppresses shear-stress-induced T-wave generation in isolated rat right atrial myocytes, with a concomitant increase in basal Ca2+ levels[2]. PSB-12054 (compound 26) (10 nM-100 μM; 30 min pre-incubation) potently inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with human P2X4 receptors with an IC50 of 0.189 μM, reaching a maximal inhibition of 77%[1]. PSB-12054 (30 min pre-incubation) inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with rat P2X4 receptors with an IC50 of 2.10 μM[1]. PSB-12054 (30 min pre-incubation) inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with mouse P2X4 receptors with an IC50 of 1.77 μM[1]. PSB-12054 (30 min pre-incubation) inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with human P2X1 receptors with an IC50 of 6.52 μM[1]. PSB-12054 (10 μM; 30 min pre-incubation) shows weak inhibition of ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with human P2X2, P2X3, and P2X7 receptors, with 13%, ~49%, and 9% inhibition respectively[1]. PSB-12054 (10-100 μM; 6 h) is hydrolytically stable under acidic, neutral, and basic conditions, showing no degradation after 6 h of incubation at relevant temperatures[1]. PSB-12054 (10 μM) shows high selectivity for P2X4 receptors, with significant interaction only observed with serotonin 5-HT2B receptors among 80 tested targets[1]. PSB-12054 inhibits human P2X4 receptors with higher potency (IC50 = 0.19 μM) than rat (IC50 = 2.10 μM) and mouse (IC50 = 1.77 μM) P2X4 receptors[3]. PSB-12054 impairs the chemotactic response of human umbilical cord blood-derived CFU-GM clonogenic progenitors to SDF-1, S1P, and eATP gradients[4]. PSB-12054 (10 μM; 30 min prior to imaging) impairs the migration of murine Sca-1+c-kit+Lin− (SKL) cells in response to ATP, reducing total migration path length and average velocity[4].
References:
[1]. Hernandez-Olmos V, et al. N-substituted phenoxazine and acridone derivatives: structure-activity relationships of potent P2X4 receptor antagonists. Journal of medicinal chemistry. 2012 Nov 26;55(22):9576-88.
[2]. Le QA, et al. Distinct shear-induced Ca signaling in the left and right atrial myocytes: Role of P2 receptor context. Journal of molecular and cellular cardiology. 2020 Jun;143:38-50.
[3]. Li B, et al. Molecular mechanism underlying the subtype-selectivity of competitive inhibitor NF110 and its distinct potencies in human and rat P2X3 receptors. Sci Bull (Beijing). 2018 Dec 30;63(24):1616-1625.
[4]. Adamiak M, et al. The P2X4 purinergic receptor has emerged as a potent regulator of hematopoietic stem/progenitor cell mobilization and homing-a novel view of P2X4 and P2X7 receptor interaction in orchestrating stem cell trafficking. Leukemia. 2022 Jan;36(1):248-256.
In Vivo, PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs HSPC homing by 40%, early engraftment by more than 50%, and delays peripheral blood cell recovery in lethally irradiated mice[4]. PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs G-CSF-induced HSPC mobilization in wild-type mice[4]. PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs short-term AMD3100-induced HSPC mobilization in wild-type mice[4]. PSB-12054 (3 mg/kg; i.p.; daily; 8 days) impairs AMD3100 (Plerixafor) -induced HSPC mobilization in P2X7-KO mice[4].
In Vitro, PSB-12054 (10 μM; 4-5 min) suppresses shear-stress-induced T-wave generation in isolated rat right atrial myocytes, with a concomitant increase in basal Ca2+ levels[2]. PSB-12054 (compound 26) (10 nM-100 μM; 30 min pre-incubation) potently inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with human P2X4 receptors with an IC50 of 0.189 μM, reaching a maximal inhibition of 77%[1]. PSB-12054 (30 min pre-incubation) inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with rat P2X4 receptors with an IC50 of 2.10 μM[1]. PSB-12054 (30 min pre-incubation) inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with mouse P2X4 receptors with an IC50 of 1.77 μM[1]. PSB-12054 (30 min pre-incubation) inhibits ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with human P2X1 receptors with an IC50 of 6.52 μM[1]. PSB-12054 (10 μM; 30 min pre-incubation) shows weak inhibition of ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with human P2X2, P2X3, and P2X7 receptors, with 13%, ~49%, and 9% inhibition respectively[1]. PSB-12054 (10-100 μM; 6 h) is hydrolytically stable under acidic, neutral, and basic conditions, showing no degradation after 6 h of incubation at relevant temperatures[1]. PSB-12054 (10 μM) shows high selectivity for P2X4 receptors, with significant interaction only observed with serotonin 5-HT2B receptors among 80 tested targets[1]. PSB-12054 inhibits human P2X4 receptors with higher potency (IC50 = 0.19 μM) than rat (IC50 = 2.10 μM) and mouse (IC50 = 1.77 μM) P2X4 receptors[3]. PSB-12054 impairs the chemotactic response of human umbilical cord blood-derived CFU-GM clonogenic progenitors to SDF-1, S1P, and eATP gradients[4]. PSB-12054 (10 μM; 30 min prior to imaging) impairs the migration of murine Sca-1+c-kit+Lin− (SKL) cells in response to ATP, reducing total migration path length and average velocity[4].
References:
[1]. Hernandez-Olmos V, et al. N-substituted phenoxazine and acridone derivatives: structure-activity relationships of potent P2X4 receptor antagonists. Journal of medicinal chemistry. 2012 Nov 26;55(22):9576-88.
[2]. Le QA, et al. Distinct shear-induced Ca signaling in the left and right atrial myocytes: Role of P2 receptor context. Journal of molecular and cellular cardiology. 2020 Jun;143:38-50.
[3]. Li B, et al. Molecular mechanism underlying the subtype-selectivity of competitive inhibitor NF110 and its distinct potencies in human and rat P2X3 receptors. Sci Bull (Beijing). 2018 Dec 30;63(24):1616-1625.
[4]. Adamiak M, et al. The P2X4 purinergic receptor has emerged as a potent regulator of hematopoietic stem/progenitor cell mobilization and homing-a novel view of P2X4 and P2X7 receptor interaction in orchestrating stem cell trafficking. Leukemia. 2022 Jan;36(1):248-256.