MRS2768

MRS2768 is a potent, selective, and metabolically stable P2Y₂ receptor agonist with an EC₅₀ of 1.89 μM for the human P2Y₂ receptor. MRS2768 activates Gq/PLC/PKC signaling, leading to downstream phosphorylation of Akt, eNOS, and ERK, with effects varying by cell type. MRS2768 inhibits ENaC via Gq/PKC/Src/Akt to promote natriuresis and lower blood pressure in the kidney. MRS2768 activates eNOS to increase NO secretion in endothelial cells. MRS2768 drives proliferation via PI3K/Akt in fibroblasts and cancer cells. MRS2768 exerts anti-apoptotic effects through PKC/Src/Akt in cardiomyocytes. MRS2768 can be applied to investigate P2Y₂-dependent pathological processes, including acute kidney injury, chronic kidney disease and renal fibrosis, DOCA-salt induced hypertension, myocardial infarction, pulmonary arterial hypertension, pancreatic cancer, cardiac fibrosis, dry eye disease, as well as shear stress-mediated vascular remodeling and atherosclerosis^{[1][2][3][4][5][6][5][8][9][10][11][12][13]}. In Vitro:MRS2768 (Compound 7) exerts agonistic activity against hP2Y₂ (EC₅₀ = 2.76 μM) in stably transfected astrocytoma cells, yet produces no response at hP2Y₄ and hP2Y₆^[1].
MRS2768 shows superior resistance to both acidic hydrolysis and ectonucleotidase-mediated degradation in 1321N1 astrocytoma cell membranes compared with native UTP^[1].
MRS2768 (Compound 30) (30 min) selectively stimulates PLC-mediated signaling via human P2Y₂ receptors with an EC₅₀ of 1.89 μM and produces no activation of hP2Y₄ or hP2Y₆ receptors in stably transfected 1321N1 human astrocytoma cells.^[2].
MRS2768 (1-50 μM; 24 h) inhibits the growth of HK-2 cells at 50 μM^[3].
MRS2768 (20 μM; 1 h) alone does not alter extracellular ATP levels in the culture medium of HK-2 cells, whereas TNF-α (Adalimumab) (HY-P9908) treatment and combined TNF-α and MRS2768 treatment significantly increase extracellular ATP levels^[3].
MRS2768 (20 μM; 1-8 h) increases the mRNA expression level of P2Y₂R in HK-2 cells^[3].
MRS2768 (20 μM; 5-60 min) significantly elevates the phosphorylation of PKC, Src, and Akt in HK-2 cells^[3].
MRS2768 (20 μM; 5 min) activates PKC, with Src and Akt as its downstream kinases in HK-2 cells^[3].
MRS2768 (20 μM; 1 h) attenuates the upregulation of cleaved PARP, caspase-3 and caspase-8, and decreases the number of TUNEL-positive apoptotic cells as well as abnormal fragmented nuclei triggered by 16 h co-incubation of TNF-α and cycloheximide (HY-12320) in HK-2 cells^[3].
MRS2768 (20 μM)-mediated P2Y₂R activation protects proximal tubular cells from apoptotic stress and TNF-α stimulation through the PI3K/Akt signaling pathway^[3].
MRS2768(10-50 μM; 1 h) dose-dependently reduces cardiomyocyte damage and death caused by prolonged hypoxia^[4].
MRS2768 (50 μM; 1 h) exerts cardioprotective effects via P2Y₂R^[4].
MRS2768 (1 μM; 30 min) significantly inhibits the activity of epithelial sodium channels (ENaC) in the apical membrane of distal nephron principal cells^[6].
MRS2768 (0.1 μM-1 mM; 24 h) significantly boosts PANC-1 cell proliferation in a concentration-dependent fashion, and its pro-proliferative activity at 1 μM after 24 h relies entirely on P2 purinergic receptors with no non-specific off-target effects, acting specifically through P2Y₂ receptors instead of other P2 subtypes^[7].
MRS2768 significantly elevates peak intracellular calcium levels in rat conjunctival goblet cells^[8].
MRS2768 (1 μM)-induced peak intracellular calcium elevation is markedly reduced after P2Y₂ receptor knockdown, while scrambled siRNA does not interfere with its calcium-stimulating effect in rat conjunctival goblet cells^[8].
MRS2768 (10 μM; 2 h)-mediated P2Y₂ receptor activation effectively stimulates tear mucin release, and its pro-secretory potency exceeds UTP and UDP in conjunctival goblet cells^[8].
MRS2768 (10 μM; 1 h) induces actin stress fiber formation in human umbilical vein endothelial cells under static culture through intact P2Y₂-integrin RGD binding interaction, and this cytoskeletal effect disappears after P2Y₂ receptor knockdown or RGD motif mutation^[9].
MRS2768 (100 nM-30 μM; 10 min) triggers concentration-dependent vasoconstriction in precontracted porcine isolated pancreatic arterial rings^[10].
MRS2768 (30 μM; 7-28 days) boosts cardiac fibroblast proliferation through selective P2Y₂ receptor activation^[11].
MRS2768 (5 μM; 30 min) markedly reduces total ENaC activity, open probability and the number of active epithelial sodium channels in renal principal cells isolated from wild-type mice^[12].
MRS2768 activates the Gαq/11-IP₃ and Akt/eNOS signaling pathways in human pulmonary arterial endothelial cells, raising nitric oxide secretion in a time- and concentration-dependent way^[13].
MRS2768 produces pulmonary vasodilatory effects and indicates P2Y₂ as a promising therapeutic target for pulmonary arterial hypertension^[13].
In Vivo:MRS2768 (25 μg/kg; i.p.; single dose)-mediated P2Y₂R activation through PKC, Src, and Akt may attenuate the IR-induced tubular inflammation and apoptosis and prevent renal dysfunction in IR-injured mice^[3].
MRS2768 (4.44 μg/kg; i.v.; single dose) preserves left ventricular systolic function, attenuates adverse left ventricular remodeling, reduces myocardial infarct size, lowers serum Troponin T and TNF-α levels, alleviates neutrophil inflammatory infiltration, and modulates phospho-c-Jun expression after myocardial infarction^[4].
MRS2768 (25 µg/kg; i.p.; once daily; until the mice were sacrificed) improves renal function, alleviates tubular injury, reduces renal fibrosis and inflammation, and normalizes abnormal JunB signaling to facilitate kidney recovery after renal ischemia-reperfusion injury^[5].
MRS2768 (5 mg/kg; i.p.; once daily) induces prominent natriuresis in mice maintained on sodium-free diet via systemic P2Y₂R activation^[6].
MRS2768 (0.2 mg/kg; i.p.; once daily; for consecutive 6 days) induces persistent and significant elevation of 24-hour urinary sodium excretion in wild-type mice maintained on sodium-restricted diet^[12].
MRS2768 (0.2 mg/kg; i.p.; once daily; given day 9 to day 12 after DOCA implantation) loses hypotensive effects in DOCA-salt hypertensive mice lacking principal cell P2Y₂ receptors, verifying renal tubular P2Y₂ is the core target mediating MRS2768 antihypertensive function^[12].