INT-777

INT-777 is a potent TGR5 agonist with an EC50 of 0.82 μM.

Signaling Pathways >> GPCR/G Protein >> GPCR19

Research Areas >> Endocrinology

EC50: 0.82 μM (TGR5)[1]

INT-777 is a novel potent and selective TGR5 agonist with remarkable in vivo activity[1]. INT-777 (3 μM) increases ATP production in the human enteroendocrine cell line NCI-H716 in a cAMP-dependent manner[2]. INT-777 (10 μM) lowers Isc and increases TEER when added on the serosal side of seromuscular stripped distal colon segments. INT-777 effect on basal secretion is reduced in neuron-free and TTX-treated mucosal-submucosal preparations[3].

INT-777 (1 μM/min/kg, p.o.) has a potent choleretic effect, prevents carboxyl CoA activation and subsequent conjugation, thereby favoring its cholehepatic shunt pathway with a ductular absorption and a potent choleretic effect in HF-fed TGR5-Tg male mice[1]. INT-777 (30 mg/kg/day, p.o.) increases energy expenditure and reduces hepatic steatosis and obesity upon high fat feeding, and improves insulin sensitivity, in TGR5-Tg mice[2].

The experiments are carried out in STC-1 or NCI-H716 cells treated with vehicle (DMSO) or INT-777. INT-777 is assessed for its agonistic activity on TGR5. cAMP production is performed. Cytochrome C oxidase activity is evaluated by following the oxidation of fully reduced cytochrome C at 550 nm. ATP/ADP ratio and GLP-1 release is measured according to the manufacturer's instruction. Primary brown adipocytes are prepared and ileal explants are prepared.

Age-matched male mice are used for all experiments. Genetically engineered mouse models (GEMMs), i.e. TGR5-Tg and TGR5-/- mice are generated. Diet-induced obesity (DIO) in the GEMMs or C57BL/6J mice is induced by feeding 8-week-old mice with a HF-diet (60%Cal/fat, D12492) for at least 8 weeks, as mentioned in the text and figure legends. In the dietary intervention experiments, INT-777 is mixed with diet at the dose sufficient to reach an in vivo dose of 30mg/kg/d. Mouse phenotyping experiments are performed according to EMPRESS protocols and aimed to assess food and water intake, body composition, energy expenditure, glucose and lipid homeostasis, and plasma biochemistry.

[1]. Pellicciari R, et al. Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J Med Chem. 2009 Dec 24;52(24):7958-61.

[2]. Thomas C, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009 Sep;10(3):167-77.

[3]. Duboc H, et al.Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons. Neurogastroenterol Motil. 2016 Jun 3. doi: 10.1111/nmo.

[4]. Baiqiang Li, et al. INT-777, a bile acid receptor agonist, extenuates pancreatic acinar cells necrosis in a mouse model of acute pancreatitis. Biochem Biophys Res Commun. 2018 Sep 3;503(1):38-44.

INT-767 | Deoxycholic acid | BAR501 | TGR5 | SB756050 | BAR502 | INT-777 R-enantiomer | Hyodeoxycholic acid