α-NETA is a non-competitive inhibitor of choline acetyltransferase (ChAT; IC50=9μM). α-NETA inhibits ALDH1A1 (IC50=0.04μM) and antagonizes the activity of chemokine-like receptor 1 (CMKLR1), cholinesterase (ChE; IC50=84μM), and acetylcholinesterase (AChE; IC50=300μM). α-NETA can be used in research related to cancer and diabetic nephropathy[1-4].
In vitro, α-NETA (5μM) pretreated human gastric cancer AGS cells for 16-24 hours. α-NETA inhibited Chemerin-induced cell migration and invasion and suppressed cell morphological transformation[5]. α-NETA (3μM) treated chemerin-overexpressing human trophoblast cells (HTR8/SVneo) for 24-48 hours. α-NETA induced cell membrane rupture, cytoplasmic leakage, and activated the GSDMD/caspase-4-mediated pyroptosis pathway by increasing the expression of caspase-4 and GSDMD and the secretion of IL-18[6].
In vivo, α-NETA (30mg/kg; once daily) was administered by gavage to high-fat diet-induced obese C57BL/6 mice for 4 weeks. α-NETA reduced body weight in the mice[7]. α-NETA (10mg/kg; three times per week) was administered via intraperitoneal injection to nude mice bearing UOK101 cell xenograft tumors and SCID mice bearing human ccRCC PDX (UTSW-XP296) models (subcutaneous and orthotopic implantation) for 70 days. α-NETA significantly inhibited tumor growth and reduced lipid deposition within the tumors, while no significant changes in animal health status were observed[8].
References:
[1] Sastry BV, Jaiswal N, Janson V, et al. Relationships between chemical structure and inhibition of choline acetyltransferase by 2-(alpha-naphthoyl)ethyltrimethylammonium and related compounds. Pharmacol Res Commun. 1988 Sep;20(9):751-71.
[2] Graham KL, Zhang JV, Lewén S, et al. A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One. 2014 Dec 1;9(12):e112925.
[3] Qiao L, Wu X, Zhang J, et al. α-NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase-4 pathway. FASEB J. 2019 Nov;33(11):12760-12767.
[4] Aleksandrov AA, Polyakova NV, Vinogradova EP, et al. The TAAR5 agonist α-NETA causes dyskinesia in mice. Neurosci Lett. 2019 Jun 21;704:208-211.
[5] Kumar JD, Aolymat I, Tiszlavicz L, et al. Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells: putative role of decreased TIMP-1 and TIMP-2. Oncotarget. 2019 Jan 4;10(2):98-112.
[6] Tan L, Chen Z, Sun F, et al. Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms. Clin Sci (Lond). 2022 Feb 25;136(4):257-272.
[7] Zheng C, Zheng Y, Chen X, et al. α-NETA down-regulates CMKLR1 mRNA expression in ileum and prevents body weight gains collaborating with ERK inhibitor PD98059 in turn to alleviate hepatic steatosis in HFD-induced obese mice but no impact on ileal mucosal integrity and steatohepatitis progression. BMC Endocr Disord. 2023 Jan 10;23(1):9.
[8] Wang D, Mahmud I, Thakur VS, et al. GPR1 and CMKLR1 Control Lipid Metabolism to Support the Development of Clear Cell Renal Cell Carcinoma. Cancer Res. 2024 Jul 2;84(13):2141-2154.
α-NETA是一种非竞争性的胆碱乙酰转移酶（ChAT；IC50=9μM）抑制剂。α-NETA可抑制ALDH1A1（IC50=0.04μM）和拮抗趋化因子样受体1（CMKLR1）、胆碱酯酶（ChE；IC50=84μM）和乙酰胆碱酯（AChE；IC50=300μM）活性。α-NETA可用于癌症和糖尿病肾病的相关研究[1-4]。
在体外，α-NETA（5μM）预处理人胃癌AGS细胞16-24小时。α-NETA可抑制Chemerin诱导的细胞迁移与侵袭，并抑制细胞形态转化[5]。α-NETA（3μM）处理过表达chemerin的人滋养细胞（HTR8/SVneo）24-48小时。α-NETA诱导细胞膜破裂、胞质泄漏，并通过增加caspase-4和GSDMD的表达及IL-18的分泌，激活了GSDMD/caspase-4介导的细胞焦亡通路[6]。
在体内，α-NETA（30mg/kg；每天一次）灌胃于高脂饮食诱导的肥胖C57BL/6小鼠4周。α-NETA降低了小鼠的体重[7]。α-NETA（10mg/kg；每周三次）腹腔注射于携带UOK101细胞异种移植瘤的裸鼠70天，以及携带人ccRCC PDX（UTSW-XP296）的SCID小鼠（皮下及原位植入模型）。α-NETA显著抑制了肿瘤生长，并减少了肿瘤中的脂质沉积，同时未观察到动物健康状况的显著变化[8]。