TM38837
目录号 : GC39666
TM38837 是一种外周选择性大麻素受体1型 (CB1) 受体拮抗剂。TM38837 对大脑的渗透率有限，以最小化或防止 CNS 不良反应，并保留潜在的抗肥胖作用。TM38837 减少精神病副作用的倾向。
Cas No.:1253641-65-4
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
TM38837 is a peripheral selective cannabinoid receptor type 1 (CB1) receptor antagonist. TM38837 shows limited penetrance to the brain in order to minimize or prevent CNS adverse reactions, and preserves potential antiobesity effects. TM38837 reduces propensity for psychiatric side effects[1][2].
[1]. Micale V, et al. The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows ReducedFear-Promoting Effects in Mice. Front Pharmacol. 2019 Mar 20;10:207. [2]. Klumpers LE, et al. Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Br J Clin Pharmacol. 2013 Dec;76(6):846-57.
| Cas No. | 1253641-65-4 | SDF | |
| Canonical SMILES | O=C(C1=NN(C2=CC=C(Cl)C=C2Cl)C(C3=CC=C(C#CC4=CC=C(C(F)(F)F)C=C4)S3)=C1CC)NN5CCCCC5 | ||
| 分子式 | C30H25Cl2F3N4OS | 分子量 | 617.51 |
| 溶解度 | DMSO: 41.67 mg/mL (67.48 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 | 1.6194 mL | 8.097 mL | 16.1941 mL |
| 5 mM | 0.3239 mL | 1.6194 mL | 3.2388 mL |
| 10 mM | 0.1619 mL | 0.8097 mL | 1.6194 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。
The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice
Front Pharmacol 2019 Mar 20;10:207.PMID:30949045DOI:10.3389/fphar.2019.00207.
Rimonabant was the first selective CB1 antagonist/inverse agonist introduced into clinical practice to treat obesity and metabolic-related disorders. It was withdrawn from market due to the notably increased rates of psychiatric side effects. We have evaluated TM38837, a novel, largely peripherally restricted CB1 antagonist, in terms of fear-promoting consequences of systemic vs. intracerebral injections. Different groups of male C57BL/6 N mice underwent auditory fear conditioning, followed by re-exposure to the tone. Mice were treated per os (p.o.) with TM38837 (10, 30, or 100 mg/kg), rimonabant (10 mg/kg; a brain penetrating CB1 antagonist/inverse agonist which served as a positive control), or vehicle, 2 h prior the tone presentation. Only the high dose of TM38837 (100 mg/kg) induced a significant increase in freezing behavior, similar to that induced by rimonabant (10 mg/kg) (p < 0.001). If injected into the brain both TM38837 (10 or 30 μg/mouse) and rimonabant (1 or 10 μg/mouse) caused a sustained fear response to the tone, which was more pronounced after rimonabant treatment. Taken together, TM38837 was at least one order of magnitude less effective in promoting fear responses than rimonabant. Given the equipotency of the two CB1 antagonists with regard to weight loss and metabolic syndrome-like symptoms in rodent obesity models, our results point to a critical dose range in which TM3887 might be beneficial for indications such as obesity and metabolic disorders with limited risk of fear-promoting effects.
Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects
Br J Clin Pharmacol 2013 Dec;76(6):846-57.PMID:23601084DOI:10.1111/bcp.12141.
Aim: Cannabinoid receptor type 1 (CB1 ) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. Methods: This was a double-blind, randomized, placebo-controlled, crossover study. On occasions 1-4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK-PD modelling. Results: The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [-26.70% [90% confidence interval (CI) -40.9, -12.6%]; -7.10%, (90%CI -18.1, 5.3%); -7.30%, (90% CI -11.5%, -3.0%) respectively] and TM38837 500 mg [-22.10% (90% CI -34.9, -9.4%); -12.20% (90% CI -21.6%, -1.7%); -8.90% (90% CI -12.8%, -5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions: Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.
Low brain CB1 receptor occupancy by a second generation CB1 receptor antagonist TM38837 in comparison with rimonabant in nonhuman primates: a PET study
Synapse 2014 Mar;68(3):89-97.PMID:24293119DOI:10.1002/syn.21721.
Both central and peripheral cannabinoid receptor type 1 (CB1R) have been considered to be among the key targets for obesity treatment. First generation CB1R antagonists/inverse agonists such as rimonabant and taranabant exhibited severe CNS side effects such as anxiety and depression, which are considered to be related to the compounds' ability to access central CB1R. Recently, several compounds have been developed as second generation antagonists with a profile of restriction to peripheral CB1R. We evaluated the distribution of TM38837, a second generation CB1R antagonist, using brain and whole body PET in three cynomolgus monkeys, and established the relationship between CB1R occupancy and dose/plasma concentration of TM38837 in comparison with rimonabant. A brain PET study was performed using [(11) C]MePPEP, a PET radioligand for CB1R, to evaluate the brain CB1R occupancy of TM38837 at various plasma concentrations in comparison with rimonabant at known efficacious plasma concentrations. A whole body PET study was performed to investigate the change of peripheral distribution of [(11) C]MePPEP by TM38837 administration, which indirectly estimated the effects to the peripheral CB1R by TM38837. CB1R occupancy by both TM38837 and rimonabant increased in a dose/plasma concentration-dependent manner. However, in vivo affinity by plasma level was more than 100 times lower for TM38837. Peripherally, [(11) C]MePPEP accumulation decreased in gall bladder and brown adipose tissue by TM38837 administration. TM38837 showed rather lower CB1R occupancy than rimonabant at the expected therapeutic plasma level, which is expected to reduce CNS side effects in clinical situations. Further clinical development of TM38837 is warranted.
Peripherally restricted CB1 receptor blockers
Bioorg Med Chem Lett 2013 Sep 1;23(17):4751-60.PMID:23902803DOI:10.1016/j.bmcl.2013.06.066.
Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).