AR420626 is an oral active and selective agonist of free fatty acid receptor 3 (FFAR3) with an EC50 value of 2.2µM [1]. AR420626 increases the release of GLP-2 and stimulates HCO3− secretion via GLP-2 receptor activation [2]. AR420626 has been widely used to alleviate ulcer formation and gastrointestinal bleeding in rat models, and to protect gastrointestinal functions[3].
In vitro, AR420626 treatment for 48 hours significantly inhibited the proliferation of HepG2 cells, with an IC50 value of 25µM[4]. Treatment with 10µM AR420626 for 24 hours significantly enhanced the mRNA expression of TPH1 and SERT in RIN-14B cells, and also inhibited the level of IDO1[5]. Treatment with 20µM AR420626 for 24 hours significantly reduced the production of lipopolysaccharide-induced nitric oxide (NO) in RAW264.7 cells without affecting cell viability[6].
In vivo, AR420626 treatment via daily intraperitoneal injection at a dose of 26.64μg/kg for one week can improve glucose tolerance in streptozotocin (STZ)-induced diabetic mice and increase plasma insulin levels[7]. Daily oral administration of a 0.1mg/kg dose of AR420626 for 8 weeks prevented the motor disorders and loss of dopaminergic neurons in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease mice[8].
References:
[1] Lee Y J, Son S E, Im D S. Free fatty acid 3 receptor agonist AR420626 reduces allergic responses in asthma and eczema in mice[J]. International Immunopharmacology, 2024, 127: 111428.
[2] Iwasaki M, Akiba Y, Kaunitz J D. Duodenal chemosensing of short-chain fatty acids: implications for GI diseases[J]. Current gastroenterology reports, 2019, 21(8): 35.
[3] Mishra S P, Karunakar P, Taraphder S, et al. Free fatty acid receptors 2 and 3 as microbial metabolite sensors to shape host health: pharmacophysiological view[J]. Biomedicines, 2020, 8(6): 154.
[4] Mikami D, Kobayashi M, Uwada J, et al. AR420626, a selective agonist of GPR41/FFA3, suppresses growth of hepatocellular carcinoma cells by inducing apoptosis via HDAC inhibition[J]. Therapeutic advances in medical oncology, 2020, 12: 1758835920913432.
[5] Liu Z, Ling Y, Peng Y, et al. Regulation of serotonin production by specific microbes from piglet gut[J]. Journal of animal science and biotechnology, 2023, 14(1): 111.
[6] Salaga M, Bartoszek A, Binienda A, et al. Activation of free fatty acid receptor 4 affects intestinal inflammation and improves colon permeability in mice[J]. Nutrients, 2021, 13(8): 2716.
[7] Lee D H, Heo K S, Myung C S. Gαi‐coupled GPR41 activation increases Ca2+ influx in C2C12 cells and shows a therapeutic effect in diabetic animals[J]. Obesity, 2023, 31(7): 1871-1883.
[8] Hou Y, Shan C, Zhuang S, et al. Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson’s disease[J]. Microbiome, 2021, 9(1): 34.
AR420626是一种口服活性、选择性的游离脂肪酸受体3(FFAR3)激动剂，EC50值为2.2µM[1]。AR420626可增加GLP-2的释放，并通过激活GLP-2受体刺激HCO3−分泌[2]。AR420626已被广泛用于减轻大鼠模型中的溃疡形成和胃肠道出血，并保护胃肠道功能[3]。
在体外，AR420626处理48小时显著抑制了HepG2细胞的增殖，IC50值为25µM[4]。10µM的AR420626处理RIN-14B细胞24小时，显著增强了TPH1和SERT的mRNA表达，同时也抑制了IDO1的水平[5]。20µM的AR420626处理RAW264.7细胞24小时，显著减少了脂多糖诱导的一氧化氮(NO)的产生，且不影响细胞活力[6]。
在体内，每日腹腔注射26.64µg/kg剂量的AR420626，持续一周，可改善链脲佐菌(STZ)诱导的糖尿病小鼠的葡萄糖耐量并增加血浆胰岛素水平[7]。每日口服0.1mg/kg剂量的AR420626，持续8周，可预防6-羟基多巴胺(6-OHDA)诱导的帕金森病小鼠的运动障碍和多巴胺能神经元丢失[8]。