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Chemical Structure| 1199796-29-6 Chemical Structure| 1199796-29-6

Structure of INT-777
CAS No.: 1199796-29-6

Chemical Structure| 1199796-29-6

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

Synonyms: S-EMCA

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Product Citations

Product Citations

Jin, Peng ; Deng, Shuixiang ; Tian, Mi ; Lenahan, Cameron ; Wei, Pengju ; Wang, Yao , et al.

Abstract: Background: Survivors of sepsis must often endure significant cognitive and behavioral impairments after discharge, but research on the relevant mechanisms and interventions remains lacking. TGR5, a member of the class A GPCR family, plays an important role in many physiological processes, and recent studies have shown that agonists of TGR5 show neuroprotective effects in a variety of neurological disorders. To date, no studies have assessed the effects of TGR5 on neuroinflammatory, cognitive, or behavioral changes in sepsis models. Methods: A total of 267 eight-week-old male Sprague-Dawley rats were used in this study. Sepsis was induced via cecal ligation and puncture (CLP). All animals received volume resuscitation. The rats were given TGR5 CRISPR oligonucleotide intracerebroventricularly 48 h before CLP surgery. INT-777 was administered intranasally 1 h after CLP, and the cAMP inhibitor, SQ22536, was administered intracerebroventricularly 1 h after CLP. Survival rate, bodyweight change, and clinical scores were assessed, and neurobehavioral tests, western blot, and immunofluorescence staining were performed. The cognitive function of rats was measured using the Morris water maze during 15–20 days after CLP. Results: The expression of TGR5 in the rat hippocampus was upregulated, and peaked at 3 days after CLP. The survival rate of rats after CLP was less than 50%, and the growth rate, in terms of weight, was significantly decreased. While INT-777 treatment did not improve these changes, the treatment did reduce the clinical scores of rats at 24 h after CLP. On day 15 and later, the surviving mice completed a series of behavioral tests. CLP rats showed spatial and memory deficits and anxiety-like behaviors, but INT-777 treatment significantly improved these effects. Mechanistically, immunofluorescence analysis showed that INT-777 treatment reduced the number of microglia in the hippocampus, neutrophilic infiltration, and the expression of inflammatory factors after CLP in rats. Moreover, INT-777 treatment significantly increased the expression of TGR5, cAMP, p-PKA, and p-CREB, but downregulated the expression of IL-1β, IL-6, and TNF-α. CRISPR-mediated TGR5 knockdown and SQ22536 treatment abolished the neuroprotective effects of TGR5 activation after CLP. Conclusion: This study demonstrates that INT-777 treatment reduced neuroinflammation and microglial cell activation, but improved cognitive impairment in the experimental sepsis rats. TGR5 has translational potential as a therapeutic target to improve neurological outcomes in sepsis survivors.

Keywords: Sepsis-associated encephalopathy ; TGR5 ; INT-777 ; Cognitive impairment ; Neuroinflammation

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Product Details of INT-777

CAS No. :1199796-29-6
Formula : C27H46O5
M.W : 450.65
SMILES Code : O[C@@H]1CC[C@@]2(C)[C@@]([C@@H](CC)[C@@H](O)[C@]3([H])[C@]2([H])C[C@H](O)[C@@]4(C)[C@@]3([H])CC[C@@H]4[C@H](C)C[C@H](C)C(O)=O)([H])C1
Synonyms :
S-EMCA
MDL No. :MFCD18837028

Safety of INT-777

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Related Pathways of INT-777

GPCR

Isoform Comparison

Biological Activity

In Vitro:

Cell Line
Concentration Treated Time Description References
Bone marrow-derived dendritic cells (BMDCs) 100 µM 24 hours To study the effect of INT-777 on the secretion of pro-inflammatory cytokines in BMDCs, results showed that INT-777 significantly inhibited the secretion of IL-6, IL-1β, IL-12/p70, IL-23, and TNF-α Int J Biol Sci. 2022 Jul 11;18(11):4545-4559.
Monocyte-derived dendritic cells (MD-DCs) 100 µM 24 hours To study the effect of INT-777 on the secretion of pro-inflammatory cytokines in MD-DCs, results showed that INT-777 significantly inhibited the secretion of TNF-α, IL-6, IL-1β, and IL-12/p70 Int J Biol Sci. 2022 Jul 11;18(11):4545-4559.

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Sprague-Dawley rats Subarachnoid hemorrhage model Intranasal administration 30 μg/kg Single dose, lasting 24 hours INT-777 significantly improved short-term neurobehavioral functions and reduced brain edema and neuroinflammation by activating the TGR5/cAMP/PKA signaling pathway Brain Behav Immun. 2021 Jan;91:587-600

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2.22mL

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0.22mL

11.10mL

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1.11mL

22.19mL

4.44mL

2.22mL

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