期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 139, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2021.111613
关键词
Dual agonist; GPR120; GPR40; GLP-1; Glucose homeostasis; Diabetes; 5280934)
资金
- Ministero per lo sviluppo economico, grant Piattaforma tecnologica integrata per l' identificazione e lo sviluppo di nuovi farmaci per il trattamento di patologie rare o ad elevato bisogno di cura insoddisfatto (PON I&C 2014/2020 D.M. 1 giugno 2016) [F/090033/01-03-04/X36]
- Ministero dell'Istruzione, Universita e della Ricerca Scientifica (grants PRIN 2017) [2017CPLH32]
New dual GPR40 and GPR120 agonist DFL23916 shows promising effects on GLP-1 secretion and glucose homeostasis, with high activity and selectivity, and potential for inducing GLP-1 secretion in vivo.
G-protein coupled receptors 40 and 120 (GPR40 and GPR120) are increasingly emerging as potential therapeutic targets for the treatment of altered glucose homeostasis, and their agonists are under evaluation for their glucagon-like peptide-1 (GLP-1)-mediated therapeutic effects on insulin production and sensitivity. Here, we characterized a new dual GPR40 and GPR120 agonist (DFL23916) and demonstrated that it can induce GLP-1 secretion and improve glucose homeostasis. Resulting from a rational drug design approach aimed at identifying new dual GPR120/40 agonists able to delay receptor internalization, DFL23916 had a good activity and a very high selectivity towards human GPR120 (long and short isoforms) and GPR40, as well as towards their mouse orthologous, by which it induced both G alpha q/ 11-initiated signal transduction pathways with subsequent Ca2+ intracellular spikes and G protein-independent signaling via beta-arrestin with the same activity. Compared to the endogenous ligand alpha-linolenic acid (ALA), a selective GPR120 agonist (TUG-891) and a well-known dual GPR40 and GPR120 agonist (GW9508), DFL23916 was the most effective in inducing GLP-1 secretion in human and murine enteroendocrine cells, and this could be due to the delayed internalization of the receptor (up to 3 h) that we observed after treatment with DFL23916. With a good pharmacokinetic/ADME profile, DFL23916 significantly increased GLP-1 portal vein levels in healthy mice, demonstrating that it can efficiently induce GLP-1 secretion in vivo. Contrary to the selective GPR120 agonist (TUG-891), DFL23916 significantly improved also glucose homeostasis in mice undergoing an oral glucose tolerance test (OGTT).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据