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G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Dec 26; Vol. 57 (24), pp. 10343-54. Date of Electronic Publication: 2014 Dec 09. - Publication Year :
- 2014
-
Abstract
- GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-α and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-α and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.
- Subjects :
- Animals
Anti-Inflammatory Agents chemistry
Calcium metabolism
Cyclic AMP metabolism
Enzyme-Linked Immunosorbent Assay
Humans
Indoles chemistry
Inflammation drug therapy
Inflammation immunology
Jurkat Cells
Lipopolysaccharides pharmacology
Macrophages drug effects
Macrophages immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes drug effects
Monocytes immunology
Niacinamide chemistry
Niacinamide pharmacology
Receptors, G-Protein-Coupled physiology
Anti-Inflammatory Agents pharmacology
Indoles pharmacology
Inflammation metabolism
Interleukin-10 metabolism
Interleukin-12 metabolism
Macrophages metabolism
Monocytes metabolism
Niacinamide analogs & derivatives
Receptors, G-Protein-Coupled agonists
Tumor Necrosis Factor-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25411721
- Full Text :
- https://doi.org/10.1021/jm501052c