催产素
兴奋剂
化学
内分泌学
内科学
受体
药理学
催产素受体
生物化学
医学
作者
Elsa Pflimlin,Zhihong Zhou,Zaid Amso,Qiangwei Fu,Candy Lee,Avinash Muppiddi,Sean B. Joseph,Vân Nguyên-Trân,Weijun Shen
标识
DOI:10.1021/acs.jmedchem.9b01862
摘要
The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.
科研通智能强力驱动
Strongly Powered by AbleSci AI