Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model
| Autor: | Jeong Hoon Kim, Sang-Bae Han, Sung Goo Park, Byoung Chul Park, Jong Soon Kang, Suresh Paudel, Sunhong Kim, Youngshin Kwak, Bi-Oh Park |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
GPR43 Chemistry Allosteric regulation Inflammation NF-κB Butyrate Biochemistry chemistry.chemical_compound Downregulation and upregulation In vivo Anti-inflammation Heterotrimeric G protein Drug Discovery medicine Molecular Medicine Original Article medicine.symptom Allosteric agonists Receptor |
| Zdroj: | Biomolecules & Therapeutics |
| ISSN: | 2005-4483 1976-9148 |
| DOI: | 10.4062/biomolther.2021.078 |
| Popis: | GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gαi/o and Gαq/11 heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca2+ flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-κB. However, GPR43 shares the same ligands as GPR41, including acetate, propionate, and butyrate, and determination of its precise functions in association with endogenous ligands, such as SCFAs alone, therefore remains a considerable challenge. In this study, we generated novel synthetic agonists that display allosteric modulatory effects on GPR43 and downregulate NF-κB activity. In particular, the potency of compound 187 was significantly superior to that of pre-existing compounds in vitro. However, in the colitis model in vivo, compound 110 induced more potent attenuation of inflammation. These novel allosteric agonists of GPR43 clearly display anti-inflammatory potential, supporting their clinical utility as therapeutic drugs. |
| Databáze: | OpenAIRE |
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