ML221 is a selective, reversible antagonist of the apelin receptor (APJ)[1]. APJ is a G protein-coupled receptor homologous to the angiotensin II receptor, widely expressed in cardiovascular, nervous, and metabolic tissues, mediating the hypotensive, positive inotropic, and angiogenic effects triggered by apelin peptides[2]. ML221 is commonly used for research into the mechanisms of cardiovascular diseases, metabolic syndrome, and renal fibrosis[3].
In vitro, ML221 (10–20μM; 24h) significantly reduced HTR8/SVneo cell migration, invasion, and tube formation, and attenuated primary extravillous trophoblasts (EVTs) migration and invasion enhanced by COL6A1 overexpression[4]. ML221 (10μM; 15min) significantly inhibited apelin-induced reductions in ROS production and increases in SOD activity in SHR cardiomyocytes[5].
In vivo, ML221 (10mg/kg; i.p.; 7 days) restored BTB integrity, increased TJP1 and GJA1 expression, and improved sperm quality and fertilization rates in db/db mice[6]. ML221 (150μg/kg; 14 days; i.p.) reversed letrozole-induced polycystic ovarian morphology in adult Swiss albino mice, reduced cyst number, restored corpus luteum formation, lowered serum testosterone and androstenedione, and normalized the LH/FSH ratio[7].
References:
[1] Maloney PR, Khan P, Hedrick M, et al. Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor. Bioorg Med Chem Lett. 2012;22(21):6656-6660.
[2] Antushevich H, Wójcik M. Review: Apelin in disease. Clin Chim Acta. 2018;483:241-248.
[3] Wang Y, Wang Y, Xue K, Gao F, Li C, Fang H. Elevated reactivity of Apelin inhibited renal fibrosis induced by chronic intermittent hypoxia. Arch Biochem Biophys. 2021;711:109021.
[4] Qi G, Gong Y, Li Y, et al. Insufficient expression of COL6A1 promotes the development of early-onset severe preeclampsia by inhibiting the APJ/AKT signaling pathway. Cell Death Discov. 2025;11(1):81.
[5] Yeves AM, Godoy Coto J, Pereyra EV, et al. Apelin/APJ signaling in IGF-1-induced acute mitochondrial and antioxidant effects in spontaneously hypertensive rat myocardium. J Physiol Biochem. 2024;80(4):949-959.
[6] Song K, Yang X, An G, et al. Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models. Nat Commun. 2022;13(1):7335.
[7] Anima B, Gurusubramanian G, Roy VK. Apelin receptor modulation mitigates letrozole-induced polycystic ovarian pathogenesis in mice. Cytokine. 2024;179:156639.
ML221是apelin受体APJ的选择性可逆拮抗剂[1]。APJ是一种与血管紧张素II受体同源的G蛋白偶联受体，广泛表达于心血管神经和代谢组织，介导apelin肽引发的降压正性肌力和血管新生效应[2]。ML221常用于心血管疾病代谢综合征和肾纤维化机制研究[3]。
体外实验中，ML221（10-20μM；24h）显著抑制HTR8/SVneo细胞迁移、侵袭和管腔形成，并减弱COL6A1过表达所增强的原代绒毛外滋养层细胞迁移与侵袭[4]。在SHR心肌细胞中，ML221（10μM；15min）显著抑制apelin诱导的ROS产生减少和SOD活性的增加[5]。
体内实验中，ML221（10mg/kg；腹腔注射；7天）恢复db/db小鼠的血睾屏障完整性，上调TJP1和GJA1表达，改善精子质量及受精率[6]。ML221（150μg/kg; 14天；腹腔注射）改善了成年瑞士白化小鼠的多囊卵巢形态，减少了囊肿数量，恢复了黄体形成，降低了血清睾酮和雄烯二酮水平，并使LH/FSH比值恢复正常[7]。