Park Chong-Woo, Han Chung-Tack, Sakaguchi Yasue, Lee Jiyoun, Youn Hwa-Young
R&D Center, Futuremedicine Co., Ltd., Seongnam, Republic of Korea.
Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
EXCLI J. 2020 Feb 12;19:187-200. doi: 10.17179/excli2019-2058. eCollection 2020.
Adenosine is a critical regulator of inflammation and fibrosis, it affects endogenous cell signaling via binding to the A adenosine receptor. FM101 is a potent, highly selective A adenosine receptor modulator that has been developed as a treatment for glaucoma and hepatitis. We determined that FM101 is a biased ligand with functional activities both as a G protein agonist and a β-arrestin antagonist. The safety of FM101 was evaluated by administering an acute dose in rats, the results indicated that the approximate lethal dose was greater than 2000 mg/kg. In a subchronic toxicity study, FM101 was administered orally once per day to rats at doses of 250, 500, and 1000 mg/kg/day over a period of 28 days. Abnormal posture, irregular respiration, decreased movement, and ear flushing were observed during the early phase of dosing, and loose stools were observed sporadically among the animals that received 500 and 1000 mg/kg/day. Body weight and food consumption were decreased in one male and one female rat in the 1000 mg/kg/day group during the first 2 weeks of observation. However, there were no test substance-related changes or adverse effects observed during our ophthalmological, clinical chemistry, urine, organ weight, and histopathological analysis. These findings indicate that no observed adverse effect level of FM101 was 1000 mg/kg/day in male and female rats.
腺苷是炎症和纤维化的关键调节因子，它通过与A腺苷受体结合来影响内源性细胞信号传导。FM101是一种强效、高选择性的A腺苷受体调节剂，已被开发用于治疗青光眼和肝炎。我们确定FM101是一种偏向性配体，兼具G蛋白激动剂和β-抑制蛋白拮抗剂的功能活性。通过对大鼠给予急性剂量来评估FM101的安全性，结果表明其近似致死剂量大于2000 mg/kg。在一项亚慢性毒性研究中，以250、500和1000 mg/kg/天的剂量，每天给大鼠口服一次FM101，持续28天。给药初期观察到姿势异常、呼吸不规则、活动减少和耳部充血，在接受500和1000 mg/kg/天剂量的动物中偶尔观察到稀便。在观察的前两周，1000 mg/kg/天组的一只雄性和一只雌性大鼠体重和食物摄入量下降。然而，在我们的眼科、临床化学、尿液、器官重量和组织病理学分析中，未观察到与受试物相关的变化或不良反应。这些结果表明，在雄性和雌性大鼠中，FM101的未观察到不良反应水平为1000 mg/kg/天。
