Zamifenacin
(Synonyms: UK-76654) 目录号 : GC61387
A muscarinic M3 receptor antagonist
Cas No.:127308-82-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Zamifenacin is an antagonist of M3 muscarinic acetylcholine receptors (Ki = 10 nM for the human receptor).1 It is selective for M3 over M1, M2, M4, and M5 receptors in radioligand binding assays using cells expressing recombinant human receptors (Kis = 55, 153, 68, and 34 nM, respectively). Zamifenacin inhibits cholecystokinin-induced small bowel motility (ED50 = 0.9 mg/kg) but does not increase heart rate (ED150 = 80.0 mg/kg) in dogs.2
1.Moriya, H., Takagi, Y., Nakanishi, T., et al.Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular glandLife Sci.64(25)2351-2358(1999) 2.Wallis, R.M.Pre-clinical and clinical pharmacology of selective muscarinic M3 receptor antagonistsLife Sci.56(11-12)861-868(1995)
| Cas No. | 127308-82-1 | SDF | |
| 别名 | UK-76654 | ||
| Canonical SMILES | N1(C[C@@H](CCC1)OC(C2=CC=CC=C2)C3=CC=CC=C3)CCC4=CC5=C(C=C4)OCO5 | ||
| 分子式 | C27H29NO3 | 分子量 | 415.52 |
| 溶解度 | 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4066 mL | 12.0331 mL | 24.0662 mL |
| 5 mM | 0.4813 mL | 2.4066 mL | 4.8132 mL |
| 10 mM | 0.2407 mL | 1.2033 mL | 2.4066 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Zamifenacin (UK-76, 654) a potent gut M3 selective muscarinic antagonist, reduces colonic motor activity in patients with irritable bowel syndrome
Aliment Pharmacol Ther 1997 Jun;11(3):561-8.PMID:9218083DOI:10.1046/j.1365-2036.1997.00189.x.
Background: Zamifenacin is a new potent gut M3 selective muscarinic antagonist developed for possible use in irritable bowel syndrome. Methods: In this multicentre, double-blind, parallel group, placebo-controlled study, the effect of a single dose of Zamifenacin 10 mg or 40 mg on both fasting (30 min) and fed (60 min) colonic motor activity was assessed in 36 patients with irritable bowel syndrome (aged 25-68 years; 19 male). Colonic motility was recorded using a five-channel solid-state catheter introduced by colonoscopy to a depth of 35 cm in an unprepared colon. Results: Zamifenacin 40 mg profoundly reduced colonic motility, particularly after the meal (P < 0.05). This was reflected by a significant reduction in the mean amplitude of contractions, number of contractions, percentage duration of contractions, activity index and the motility index (P < 0.05). A smaller reduction in all the motility parameters was obtained with 10 mg Zamifenacin, but these changes were not statistically significant. Three patients each on placebo and Zamifenacin reported side-effects, but these were mild and transient. Conclusion: A single 40 mg dose of Zamifenacin significantly reduces colonic motility in irritable bowel syndrome patients without significant antimuscarinic effects. The results of this study confirm that the concept of developing selective antimuscarinic agents may be a promising approach to the treatment of irritable bowel syndrome. Not only would such compounds benefit from not having the usual side-effects of anticholinergics but they might also offer much more in the way of dose flexibility.
Characterization of the interaction of Zamifenacin at muscarinic receptors in vitro
Eur J Pharmacol 1995 Oct 16;285(2):135-42.PMID:8566131DOI:10.1016/0014-2999(95)00394-z.
The interaction of Zamifenacin ((3R)-(+)-diphenylmethoxy-1-(3,4)-methylenedioxyphenethyl)pi peridine) at muscarinic receptor subtypes was studied using radioligand binding and functional techniques, in vitro. In radioligand binding studies, Zamifenacin acted as a competitive antagonist, with the following pKi values; rat cerebral cortex (M1) 7.90 +/- 0.08, myocardium (M2) 7.93 +/- 0.13, submaxillary gland (M3) 8.52 +/- 0.04 and rabbit lung (M4) 7.78 +/- 0.04. In functional studies Zamifenacin acted as a surmountable antagonist, exhibiting the following apparent affinity values; canine saphenous vein (putative M1) 7.93 +/- 0.09, guinea-pig left atria (M2) 6.60 +/- 0.04, guinea-pig ileum (M3) 9.31 +/- 0.06, guinea-pig oesophageal muscularis mucosae (M3) 8.84 +/- 0.04, guinea-pig trachea (M3) 8.16 +/- 0.04, and guinea-pig urinary bladder (M3) 7.57 +/- 0.15. Therefore, Zamifenacin is selective for muscarinic M3 receptors in guinea-pig ileum, oesophageal muscularis mucosae, trachea and bladder over muscarinic M2 receptors in atria. The degree of muscarinic M3/M2 receptor selectivity depends upon the muscarinic M3 receptor preparation studied.
In vitro toxicity of Zamifenacin (UK-76,654) and metabolites in primary hepatocyte cultures
Xenobiotica 1998 Sep;28(9):895-908.PMID:9764931DOI:10.1080/004982598239137.
1. We compared the sensitivities of primary hepatocytes from rat, dog and monkey to Zamifenacin and two major metabolites, the methylenedioxy ring-opened catechol, UK-80,178 and its methylated product, UK-82,201. Toxicity was determined both via neutral red uptake and enzyme leakage data. 2. Canine hepatocytes were most sensitive to the cytotoxic effects of Zamifenacin during 24-h exposure. Significant decreases in medium concentrations of Zamifenacin in the presence of primary hepatocytes verified cellular uptake during the initial 2-h incubation. All three cell types were much more sensitive to UK-82,201 than to the catechol metabolite or parent drug. 3. The rapid onset of cytotoxicity indicated by elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and other markers in the medium after UK-82,201 exposure, the delayed but substantial cytotoxic response to the parent drug which was suggestive of biotransformation to a reactive moiety, in vivo and in vitro drug metabolism results and subacute toxicology data suggest that dog may more effectively transform Zamifenacin into UK-82,201, which is relatively hepatotoxic. 4. Because the catechol was generally less toxic than the O-methylated product, species that eliminate Zamifenacin primarily as the catechol or its conjugate may be less affected by the potential hepatotoxicity of the methylated product. Our studies show that dog is the most sensitive species due to metabolism of the common catechol metabolite. The low incidence of potential hepatotoxicity in the clinic points to rare but important differences in the metabolism of Zamifencin. We conclude that the findings in dog were not predictive of subsequent effects in man.
Pharmacokinetics and metabolism of Zamifenacin in mouse, rat, dog and man
Xenobiotica 1996 Apr;26(4):459-71.PMID:9173686DOI:10.3109/00498259609046724.
1. Zamifenacin was rapidly metabolized in vitro by liver microsomes from rat, dog, and man. 2. Zamifenacin exhibited extensive plasma protein binding with human plasma showing 20 and 10-fold higher binding that that in rat and dog respectively. 3. Following oral administration to animals, metabolic clearance resulted in decreased bioavailability due to first-pass metabolism in rat and mouse. Oral clearance in man was low as a result of increased metabolic stability and increased plasma protein binding compared with animals. 4. Metabolism was the major route of clearance of Zamifenacin with the primary metabolic step resulting in opening of the methylenedioxy ring to yield the catechol. In man, this metabolite was excreted as the glucuronide conjugate, whereas in the animal species it was further metabolized by mono-methylation of the catechol.
Computerized planimetry in the objective assessment of the antispasmodic effect of Zamifenacin in double contrast barium enemas
Br J Radiol 1996 Apr;69(820):301-5.PMID:8665128DOI:10.1259/0007-1285-69-820-301.
A prospective, randomized, double-blind study was undertaken to evaluate Zamifenacin 30 mg (Pfizer Ltd), a novel, orally-administered, gut-specific muscarinic receptor antagonist, as an adjuvant to the double contrast barium enema examination (DCBE). Zamifenacin was compared with placebo in terms of side-effects and colonic tone. Analysis of colonic tone was carried out by two independent observers, using a subjective grading system and also by an objective method using computerized planimetry. Interobserver variability was also assessed. Zamifenacin is safe and well tolerated but at the prescribed dose is an ineffective antispasmodic for DCBE. Subjective assessment of colonic tone was shown to be of limited value whilst the objective analysis using computerized planimetry was reliable and highly reproducible.