Cargando…

Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus

Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Xuekun, Li, Xu, Wei, Shiting, Wang, Min, Xu, Yao, Hu, Weidi, Gao, Zhenzhen, Liu, Renmin, Wang, Shiben, Ji, Guoxia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781217/
https://www.ncbi.nlm.nih.gov/pubmed/36558150
http://dx.doi.org/10.3390/molecules27249018
_version_ 1784857019779383296
author Wang, Xuekun
Li, Xu
Wei, Shiting
Wang, Min
Xu, Yao
Hu, Weidi
Gao, Zhenzhen
Liu, Renmin
Wang, Shiben
Ji, Guoxia
author_facet Wang, Xuekun
Li, Xu
Wei, Shiting
Wang, Min
Xu, Yao
Hu, Weidi
Gao, Zhenzhen
Liu, Renmin
Wang, Shiben
Ji, Guoxia
author_sort Wang, Xuekun
collection PubMed
description Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to β-oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds, 14d showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound 14d displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound 14d could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound 14d may be a promising lead compound deserving of further biological evaluation and structural modifications.
format Online
Article
Text
id pubmed-9781217
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-97812172022-12-24 Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus Wang, Xuekun Li, Xu Wei, Shiting Wang, Min Xu, Yao Hu, Weidi Gao, Zhenzhen Liu, Renmin Wang, Shiben Ji, Guoxia Molecules Article Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to β-oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds, 14d showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound 14d displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound 14d could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound 14d may be a promising lead compound deserving of further biological evaluation and structural modifications. MDPI 2022-12-17 /pmc/articles/PMC9781217/ /pubmed/36558150 http://dx.doi.org/10.3390/molecules27249018 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Xuekun
Li, Xu
Wei, Shiting
Wang, Min
Xu, Yao
Hu, Weidi
Gao, Zhenzhen
Liu, Renmin
Wang, Shiben
Ji, Guoxia
Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus
title Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus
title_full Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus
title_fullStr Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus
title_full_unstemmed Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus
title_short Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus
title_sort discovery of novel and selective g-protein coupled receptor 120 (gpr120) agonists for the treatment of type 2 diabetes mellitus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781217/
https://www.ncbi.nlm.nih.gov/pubmed/36558150
http://dx.doi.org/10.3390/molecules27249018
work_keys_str_mv AT wangxuekun discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT lixu discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT weishiting discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT wangmin discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT xuyao discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT huweidi discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT gaozhenzhen discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT liurenmin discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT wangshiben discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus
AT jiguoxia discoveryofnovelandselectivegproteincoupledreceptor120gpr120agonistsforthetreatmentoftype2diabetesmellitus