Loxiglumide (CR-1505)
(Synonyms: 氯谷胺,CR-1505) 目录号 : GC31382
A CCK receptor antagonist
Cas No.:107097-80-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Rats[1] At 24 h after induction of acute hemorrhagic pancreatitis, rats are divided into four different treatment groups: standard rat chow (AP-C); standard rat chow with pancreatic rest (AP-R); standard rat chow with pancreatic stimulation (AP-S); and standard rat chow with pancreatic rest, followed by pancreatic stimulation (AP-R/S). Rats in the AP-C group receive 2 mL/kg body weight saline orally (po) via an orogastric tube twice daily (09:00 and 21:00 h) for 10 d; the AP-R group receive 50 mg/kg body weight of CCK-1 receptor antagonist Loxiglumide dissolved in 2 mL distilled water po twice daily for 10 d; the AP-S group receive 25 mg/kg body weight protease inhibitor Camostat, which is known to stimulate endogenous CCK release, dissolved in 2 mL distilled water po twice daily for 10 d; and the AP-R/S group receive 50 mg/kg body weight Loxiglumide twice daily for the first 5 d followed by 25 mg/kg body weight camostat twice daily for the next 5 d. Rats are fed ad libitum. On day 12 at 24 h after the last treatment and overnight fasting, pancreatic exocrine function and histological examination of the pancreas are performed. |
References: [1]. Jia D, et al. Effect of endogenous cholecystokinin on the course of acute pancreatitis in rats. World J Gastroenterol. 2015 Jul 7;21(25):7742-53. | |
Loxiglumide is a cholecystokinin (CCK) receptor antagonist that inhibits CCK-8 binding to central and peripheral CCK receptors with Ki values of 9.1 and 0.33 μM, respectively.1 It inhibits CCK-8-induced release of acetylcholine from isolated guinea pig gallbladder (IC50 = 10 nM).2 Loxiglumide (50 μM) reduces the invasion of PANC-1 and MiaPaCa-2 human pancreatic cancer cells by 83.1 and 82.9%, respectively, in vitro.3 Loxiglumide (10-5,000 μM) reduces DNA synthesis in PC-TI and PC-YY human pancreatic cancer cells in a concentration-dependent manner (IC50s = 160 and 74 μM, respectively).4 It reduces the tumor growth rate by 37.5 and 38%, respectively, in PC-TI and PC-YY mouse xenograft models when administered at a dose of 250 mg/kg. Loxiglumide is toxic to mice with LD50 values ranging from 440 to 500 mg/kg dependent on the route of administration. In a rat model of acute pancreatitis, loxiglumide (50 mg/kg, s.c.) reduces serum concentrations of CCK, amylase, and lipase by greater than 60%, as well as tissue hemorrhaging and acinar cell necrosis.5
1.Setnikar, I., Bani, M., Cereda, R., et al.Pharmacological characterisation of a new potent and specific nonpolypeptidic cholecystokinin antagonistArzneimittelforschung37(6)703-707(1987) 2.Rakovska, A., Sgaragli, G., Mantovani, P., et al.Effect of loxiglumide (CR 1505) on CCK-induced contractions and 3H-acetylcholine release from guinea-pig gallbladderNeuropeptides25(5)271-276(1993) 3.Hirata, M., Itoh, M., Tsuchida, A., et al.Cholecystokinin receptor antagonist, loxiglumide, inhibits invasiveness of human pancreatic cancer cell linesFEBS. Lett.383(3)241-244(1996) 4.Nio, Y., Tsubono, M., Morimoto, H., et al.Loxiglumide (CR 1 505), a cholecystokinin antagonist, specifically inhibits the growth of human pancreatic cancer lines xenografted into nude miceCancer72(12)3599-3606(1993) 5.Tani, S., Itoh, H., Koide, M., et al.Involvement of endogenous cholecystokinin in the development of acute pancreatitis induced by closed duodenal loopPancreas8(1)109-115(1993)
| Cas No. | 107097-80-3 | SDF | |
| 别名 | 氯谷胺,CR-1505 | ||
| Canonical SMILES | O=C(O)CCC(NC(C1=CC=C(Cl)C(Cl)=C1)=O)C(N(CCCOC)CCCCC)=O | ||
| 分子式 | C21H30Cl2N2O5 | 分子量 | 461.38 |
| 溶解度 | DMSO : ≥ 150 mg/mL (325.11 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1674 mL | 10.8371 mL | 21.6741 mL |
| 5 mM | 0.4335 mL | 2.1674 mL | 4.3348 mL |
| 10 mM | 0.2167 mL | 1.0837 mL | 2.1674 mL |
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Inhibitory effect of loxiglumide (CR 1505), a cholecystokinin receptor antagonist, on N-nitrosobis(2-oxopropyl) amine-induced biliary carcinogenesis in Syrian hamsters
We evaluated the cholecystokinin (CCK) receptor antagonist loxiglumide (CR1505) for a possible inhibitory effect on biliary carcinogenesis in a hamster model. Experimental group I underwent cholecystoduodenostomy and ligation of the distal end of the common bile duct, after which the animals were injected with N-nitrosobis(2-oxopropyl)amine (BOP) alone. Group II, after the same surgical procedure as in group I, were given injections of BOP and then given loxiglumide in their diet. The sham-operated group underwent simple laparotomy and then were given injections of BOP. Loxiglumide significantly inhibited BOP carcinogenicity in the gallbladder and extrahepatic bile duct but not in the intrahepatic bile ducts or pancreas. Autoradiography showed that loxiglumide significantly suppressed (125)I-Bolton-Hanter (BH)-CCK-8 binding to CCK receptors in the gallbladder and extrahepatic bile duct but not in the liver or pancreas, and CCK binding to its receptors was observed in an area identified as cancer tissue. CCK receptor antagonists have an inhibitory effect on BOP carcinogenesis in the extrahepatic biliary tract, including the gallbladder and extrahepatic bile duct, of Syrian hamsters. The difference in the inhibitory effect of loxiglumide on biliary carcinogenesis in hamsters according to site may be due to differences in CCK receptors or the affinity of loxiglumide for such biliary tract organs. A difference between carcinogenesis in the intrahepatic bile ducts and extrahepatic biliary tract may be another reason.
Inhibitory effects of a cholecystokinin antagonist, loxiglumide (CR-1505), on the growth of freshly separated and xenografted human pancreatic cancer
The effects of cholecystokinin (CCK) and a CCK antagonist, loxiglumide (CR-1505), on four freshly separated and six xenografted human pancreatic cancers, were investigated. The level of DNA synthesis in only one of five tested pancreatic cancers was enhanced by CCK at concentrations of 0.01-10 nM, while in the other four cancers DNA synthesis was not affected. The levels of DNA, RNA, and protein synthesis (by 3H-thymidine, 3H-uridine, and 3H-leucine incorporation tests, respectively) in all the tested cancers were dose-dependently inhibited by loxiglumide at concentrations of 20-2000 microM, and the IC50 of loxiglumide for DNA synthesis in pancreatic cancers was 156 +/- 80 microM (means +/- SD). The in vivo effect of loxiglumide was assessed using a xenografted line (PC-HN) transplanted in nude mice. The in vivo 50% lethal dose of loxiglumide for nude mice was about 500 mg/kg. Death was caused by respiratory failure due to severe congestion of the lung after the administration of a large dose of loxiglumide. The growth of a PC-HN transplanted in the nude mice was significantly inhibited by subcutaneous loxiglumide at 250 mg/kg, twice a day for 28 days, which did not cause death. It is suggested that loxiglumide inhibits the in vivo and in vitro growth of human pancreatic cancer, perhaps independently of its action as a CCK antagonist, and this study also suggests that loxiglumide may be a new type of therapeutic agent to be used for the treatment of human pancreatic cancer.
Effect of loxiglumide (CR 1505) on CCK-induced contractions and 3H-acetylcholine release from guinea-pig gallbladder
Release of [3H]-acetylcholine (3H-ACh) and muscle contractions in response to cholecystokinin (CCK) were measured and recorded simultaneously from isolated guinea-pig gallbladder. Cholecystokinin octapeptide (CCK8) (10(-10)-10(-7) M) enhanced the release of [3H]ACh and the contractions of the muscle. TTX (10(-6) M) inhibited the CCK-induced release of 3H-ACh by only 30%. In Ca(2+)-free medium CCK8 had no effect. Loxiglumide, (CR 1505), a newly synthesized nonpeptide CCK-A-receptor antagonist, D.L-(3,4-dichlorbenzoilamino)-5-/N-(3-methoxypropyl)-pentylamin o-5-oxo-pentanoi c acid, antagonized both the ACh-releasing effect of CCK and the contractions in a dose-dependent manner. The affinity (pA2) of CR 1505 to CCK-receptors, determined by the shift of the concentration-response curves for CCK8 was 8.36. It was 5 logarithmic orders higher than the pA2 of proglumide. The IC50 value of CR 1505 calculated by the CCK-induced release of 3H-ACh was 10 nM. The results suggest the existence not only of muscular CCK receptors but also neuronal receptors for CCK probably located on cholinergic nerves.
Effect of loxiglumide (CR-1505) on bombesin- and meal-stimulated plasma cholecystokinin in man
Cholecystokinin (CCK)-receptor antagonists have been reported to inhibit the effects of the hormone on the gastrointestinal tract. Their effect on plasma CCK levels in man has not been described. The present study in 5 normal subjects demonstrated that i.v. infusion of the potent, specific CCK-receptor antagonist loxiglumide (CR 1505) significantly augmented plasma CCK levels during infusion of bombesin (402 pM per 30 min) and after administration of a meal (1390 pM per 300 min) when compared to the bombesin- (192 pM per 30 min) and meal- (886 pM per 300 min) stimulated CCK responses during infusion of saline. The basal plasma CCK during saline infusion (0.1 pM per 40 min) was not significantly influenced by CR 1505 (-1.8 pM per 40 min). Thus, both enteral (meal) and parenteral (bombesin) stimulation of CCK secretion are augmented by CCK-receptor blockade.
The effect of loxiglumide (CR-1505) on basal and bombesin-stimulated gallbladder volume in man
This study was undertaken in 5 normal subjects to determine the role of cholecystokinin (CCK) in the regulation of basal gallbladder volume and gallbladder contraction stimulated by infusion of bombesin. Administration of the CCK-receptor antagonist, loxiglumide (CR-1505), led to doubling of the gallbladder volume (increase 104 +/- 26%; P less than 0.05) and reduced the bombesin-stimulated gallbladder contraction from 69 +/- 17 to 19 +/- 17% (P less than 0.05). The findings provide evidence suggesting that CCK plays an important role in the regulation of basal gallbladder tone and in mediating the gallbladder contraction induced by the administration of bombesin.