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Gastrin/CCK antagonist 1 Sale

目录号 : GC30680

Gastrin/CCKantagonist1是gastrin/CCK的拮抗剂,可用于肠胃失调疾病的研究。

Gastrin/CCK antagonist 1 Chemical Structure

Cas No.:162271-52-5

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1mg
¥14,280.00
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5mg
¥35,700.00
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10mg
¥60,690.00
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产品描述

Gastrin/CCK antagonist 1 is an antagonist of gastrin/CCK, used for the research of gastrointestinal disorders.

[1]. 1,5 BENZODIAZEPINE DERIVATIVES HAVING CCK AND/OR GASTRIN ANTAGONISTIC ACTIVITY. WO1994024151 A1

Chemical Properties

Cas No. 162271-52-5 SDF
Canonical SMILES O=C(NC1=CC=C(F)C=C1)NC2C(N(C3CCCCC3)C4=CC=CC=C4N(CC(N5CCCC5)=O)C2=O)=O
分子式 C28H32FN5O4 分子量 521.58
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mM 1.9173 mL 9.5863 mL 19.1725 mL
5 mM 0.3835 mL 1.9173 mL 3.8345 mL
10 mM 0.1917 mL 0.9586 mL 1.9173 mL
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Research Update

Gastrin/CCK-B Receptor Signaling Promotes Cell Invasion and Metastasis by Upregulating MMP-2 and VEGF Expression in Gastric Cancer

Accumulated evidence suggests that a functional loop composed of gastrin and cholecystokinin B receptor (CCK-BR) may exist in gastric carcinogenesis. However, this suggestion is not completely supported due to a lack of direct evidence, and the underlying mechanism is not completely understood. Here, we evaluated the effects of gastrin/CCK-BR signaling on the cell growth, invasion, and expression of MMP-2 and VEGF, as well as xenograft growth in vivo. Furthermore, we detected gastrin mRNA content in human gastric cancer tissues, metastatic lymph nodes, and adjacent nontumor tissues. We found that the forced gastrin could promote the proliferation, migration, and invasion of gastric cancer cells by upregulating the expression of MMP-2 and VEGF. Blocking gastrin/CCK-BR signal using either Proglumide, a CCK-BR antagonist, or shRNA against GASTRIN significantly inhibited the gastrin-promoting effects. In vivo study revealed that the tumor growth in nude mice inoculated with gastrin-overexpressed cells was significantly faster than control cells. The gastrin mRNA content in metastatic lymph nodes was higher in patients with gastric cancer than in primary gastric cancer and adjacent nontumor tissues. In conclusion, we provided direct evidence and possible mechanism of gastrin/CCK-BR signaling in the initiation and progression of gastric cancer.

(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): a potent and orally active gastrin/CCK-B antagonist

A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in vivo included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N-[1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyri dyl) -1H-1,4-benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N-[1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5- (2-pyridyl)-1H-1,4-benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl ]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21nmol/kg po in dogs. 15c is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).

The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression

YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (±0.06). YF476 raised pH to 3.67 (±0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.

Gastrin and Gastric Cancer

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review the role of gastrin and its pathway in gastric cancer and its potential as a therapeutic target in the management of gastric cancer. In the normal adult stomach, gastrin is synthesized in the G cells of the antrum; however, gastrin expression also is found in many gastric adenocarcinomas of the stomach corpus. Gastrin's actions are mediated through the G-protein-coupled receptor cholecystokinin-B (CCK-B) on parietal and enterochromaffin cells of the gastric body. Gastrin blood levels are increased in subjects with type A atrophic gastritis and in those taking high doses of daily proton pump inhibitors for acid reflux disease. In experimental models, proton pump inhibitor-induced hypergastrinemia and infection with Helicobacter pylori increase the risk of gastric cancer. Understanding the gastrin:CCK-B signaling pathway has led to therapeutic strategies to treat gastric cancer by either targeting the CCK-B receptor with small-molecule antagonists or targeting the peptide with immune-based therapies. In this review, we discuss the role of gastrin in gastric adenocarcinoma, and strategies to block its effects to treat those with unresectable gastric cancer.

Pharmacological profile of (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo- 5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), a new potent and selective gastrin/cholecystokinin-B receptor antagonist, in vitro and in vivo

(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022) is an extremely potent and highly selective gastrin/cholecystokinin (CCK)-B receptor antagonist. We compared the gastrin/CCK-B receptor-blocking properties of this compound with those of the racemate (mixture of YM022 and its S-form), its enantiomer (S-form), L-365, 260 and Cl-988 in vitro and in vivo. YM022 replaced specific binding of [125I]CCK-8 to rat brain gastrin/CCK-B receptors in a stereoselective and competitive manner. The Ki value of YM022 for gastrin/CCK-B receptors in brain were estimated to be 0.068 nM. The racemate, the S-form of YM022, L-365,260 and Cl-988 also replaced gastrin/CCK-B receptor binding, with Ki values of 0.11, 140, 19 and 6.3 nM, respectively. The affinity of YM022 for gastrin/CCK-B receptor was more than 2 orders of magnitude higher than that for rat pancreatic CCK-A receptor and various other receptors, such as benzodiazepine. In vivo, intravenous (i.v.) administration of YM022 inhibited pentagastrin-induced gastric acid secretion in anesthetized rats, with an ED50 value of 0.0078 mumol/kg. Inhibition by the S-form of YM022 was only 33.8% even at the relatively high dose of 1 mumol/kg i.v. L-365,260 (1-10 mumol/kg i.v.) and Cl-988 (0.3-3 mumol/kg i.v.) also antagonized acid secretion induced by pentagastrin, with ED50 values of 4.23 and 1.01 mumol/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)