VU0119498
(Synonyms: 1-(4-溴苄基)吲哚-2,3-二酮) 目录号 : GC61377
An M1, M3, and M5 muscarinic receptor positive allosteric modulator
Cas No.:79183-37-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
VU0119498 is a positive allosteric modulator (PAM) of M1, M3, and M5 muscarinic acetylcholine receptors (mAChRs; EC50s = 6.04, 6.38, and 4.08 ?M, respectively, in calcium mobilization assays).1 It is selective for M1, M3, and M5 mAChRs over M2 and M4 mAChRs in CHO cells expressing the human receptors. VU0119498 (20 ?M) enhances ACh-induced insulin secretion in MIN6-K8 pancreatic β-cells.2 It decreases glucose tolerance and increases insulin secretion in mice fed normal chow, as well as in a mouse model of high-fat diet-induced obesity, when administered at a dose of 0.5 mg/kg.
1.Bridges, T.M., Marlo, J.E., Niswender, C.M., et al.Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatinsJ. Med. Chem.52(11)3445-3448(2009) 2.Zhu, L., Rossi, M., Cohen, A., et al.Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese miceProc. Natl. Acad. Sci. U.S.A.116(37)18684-18690(2019)
| Cas No. | 79183-37-2 | SDF | |
| 别名 | 1-(4-溴苄基)吲哚-2,3-二酮 | ||
| Canonical SMILES | O=C1N(C2=C(C1=O)C=CC=C2)CC3=CC=C(C=C3)Br | ||
| 分子式 | C15H10BrNO2 | 分子量 | 316.15 |
| 溶解度 | DMSO: 50 mg/mL (158.15 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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| 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 | 3.1631 mL | 15.8153 mL | 31.6306 mL |
| 5 mM | 0.6326 mL | 3.1631 mL | 6.3261 mL |
| 10 mM | 0.3163 mL | 1.5815 mL | 3.1631 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 | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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。
Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice
Proc Natl Acad Sci U S A 2019 Sep 10;116(37):18684-18690.PMID:31451647DOI:10.1073/pnas.1904943116.
Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.
Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators
Bioorg Med Chem Lett 2010 Oct 1;20(19):5617-22.PMID:20801651DOI:10.1016/j.bmcl.2010.08.042.
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative parallel synthesis approach was employed to incorporate basic heterocycles to improve physiochemical properties.
Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM
Bioorg Med Chem Lett 2010 Mar 15;20(6):1972-5.PMID:20156687DOI:10.1016/j.bmcl.2010.01.109.
This Letter describes a chemical lead optimization campaign directed at VU0119498, a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) with the goal of developing a selective M(1) PAM. An iterative library synthesis approach delivered a potent (M(1) EC(50)=830 nM) and highly selective M(1) PAM (>30 microM vs M(2)-M(5)).
Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM
Bioorg Med Chem Lett 2010 Jan 15;20(2):558-62.PMID:20004578DOI:10.1016/j.bmcl.2009.11.089.
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.
Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins
J Med Chem 2009 Jun 11;52(11):3445-8.PMID:19438238DOI:10.1021/jm900286j.
This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.