VU0152099
(Synonyms: 3-氨基-N-(苯并[D][1,3]二氧戊环-5-基甲基)-4,6-二甲基噻吩并[2,3-B]吡啶-2-甲酰胺) 目录号 : GC63630
VU0152099 是一种有效、选择性和可透过血脑屏障的 mAChR M4 正变构调节剂，对大鼠 M4 受体的 EC50 为 0.4 µM。VU0152099 对其他 mAChR 亚型或其他 GPCR 无活性。VU0152099 没有激动剂活性，但增强了 M4 对乙酰胆碱的反应。
Cas No.:612514-42-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
VU0152099 is a potent, selective and brain-penetrant mAChR M4 positive allosteric modulator with an EC50 of 0.4 µM for rat M4 receptor. VU0152099 is inactive for other mAChR subtypes or other GPCRs. VU0152099 has no agonist activity but potentiated responses of M4 to acetylcholine[1].
VU0152099 (30 µM) induces a dose-dependent leftward shift of the acetylcholine (ACh) concentration response curve (CRC) with maximal shifts of 30-fold observed with 30 µM. VU0152099 dose-dependently potentiates the response to an EC20 concentration of ACh with EC50 values of 1.2 µM, and increases the maximal response to ACh to approximately 130%. VU0152099 is a potent positive allosteric modulator that enhance the response of the M4 receptor to the endogenous agonist ACh[1].
VU0152099 (56.6 mg/kg; i.p.; once) reverses Amphetamine-induced hyperlocomotion in rats[1].
[1]. Ashley E Brady, et al. Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J Pharmacol Exp Ther. 2008 Dec;327(3):941-53.
| Cas No. | 612514-42-8 | SDF | |
| 别名 | 3-氨基-N-(苯并[D][1,3]二氧戊环-5-基甲基)-4,6-二甲基噻吩并[2,3-B]吡啶-2-甲酰胺 | ||
| 分子式 | C18H17N3O3S | 分子量 | 355.41 |
| 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 | 2.8137 mL | 14.0683 mL | 28.1365 mL |
| 5 mM | 0.5627 mL | 2.8137 mL | 5.6273 mL |
| 10 mM | 0.2814 mL | 1.4068 mL | 2.8137 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。
Effects of acute and repeated administration of the selective M4 PAM VU0152099 on cocaine versus food choice in male rats
Addict Biol 2022 Mar;27(2):e13145.PMID:35229940DOI:10.1111/adb.13145.
Ligands that stimulate muscarinic acetylcholine receptors 1 and 4 (M1 , M4 ) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M4 stimulation, as well as long-lasting, delayed reductions in cocaine taking and cocaine seeking with combined M1 /M4 receptor stimulation or with M1 stimulation alone. M4 stimulation opposes dopaminergic signalling acutely, but direct dopamine receptor antagonists have proved unhelpful in managing cocaine use disorder because they lose efficacy with long-term administration. It is therefore critical to determine whether M4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer to obtain quantitative measurement of whether M4 stimulation could produce delayed and lasting reduction in cocaine taking. VU0152099 produced progressively augmenting suppression of cocaine choice and cocaine intake, but produced neither rebound nor lasting effects after treatment ended. To compare and contrast effects of M1 versus M4 stimulation, we tested whether the M4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signalling factor, required for M1 -mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M4 -mediated suppression of cocaine self-administration. These findings support the potential usefulness of M4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M1 -selective ligands, and show that M1 and M4 stimulation modulate cocaine-taking behaviour by distinct mechanisms.
Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats
J Pharmacol Exp Ther 2008 Dec;327(3):941-53.PMID:18772318DOI:10.1124/jpet.108.140350.
Previous clinical and animal studies suggest that selective activators of M(1) and/or M(4) muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment of schizophrenia and Alzheimer's disease. However, highly selective centrally penetrant activators of either M(1) or M(4) have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. We previously identified VU10010 [3-amino-N-(4-chlorobenzyl)-4, 6-dimethylthieno[2,3-b]pyridine-2-carboxamide] as a potent and selective allosteric potentiator of M(4) mAChRs. However, unfavorable physiochemical properties prevented use of this compound for in vivo studies. We now report that chemical optimization of VU10010 has afforded two centrally penetrant analogs, VU0152099 [3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide] and VU0152100 [3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide], that are potent and selective positive allosteric modulators of M(4). VU0152099 and VU0152100 had no agonist activity but potentiated responses of M(4) to acetylcholine. Both compounds were devoid of activity at other mAChR subtypes or at a panel of other GPCRs. The improved physiochemical properties of VU0152099 and VU0152100 allowed in vivo dosing and evaluation of behavioral effects in rats. Interestingly, these selective allosteric potentiators of M(4) reverse amphetamine-induced hyperlocomotion in rats, a model that is sensitive to known antipsychotic agents and to nonselective mAChR agonists. This is consistent with the hypothesis that M(4) plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M(4) may mimic some of the antipsychotic-like effects of less selective mAChR agonists.