CP-601927
目录号 : GC63582
CP-601927 是一种选择性的 α4β2 nAChR 部分激动剂(Ki=1.2 nM; EC50=2.6 μM)。CP-601927 具有良好的脑渗透性以及具有抗抑郁样特性。
Cas No.:357425-02-6
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
CP-601927 is a selective α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist (Ki=1.2 nM; EC50=2.6 μM). CP-601927 shows good brain penetration and antidepressant-like properties[1][2].
CP-601927 (0.125 mg/kg-1.5 mg/kg; i.p.; C57BL/6J male mice) has antidepressant-like activity in animal models[2].
[1]. Campion SN, et al. Toxicity study in juvenile rats with the α4β2 nicotinic acetylcholine receptor partial agonist CP-601,927. Birth Defects Res B Dev Reprod Toxicol. 2011;92(4):323-332.
[2]. Mineur YS, et al. α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties. Behav Pharmacol. 2011;22(4):291-299.
| Cas No. | 357425-02-6 | SDF | |
| 分子式 | C12H12F3N | 分子量 | 227.23 |
| 溶解度 | DMSO : 200 mg/mL (880.17 mM; Need ultrasonic) | 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 | 4.4008 mL | 22.0041 mL | 44.0083 mL |
| 5 mM | 0.8802 mL | 4.4008 mL | 8.8017 mL |
| 10 mM | 0.4401 mL | 2.2004 mL | 4.4008 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 contribution of agonist and antagonist activities of α4β2* nAChR ligands to smoking cessation efficacy: a quantitative analysis of literature data
Psychopharmacology (Berl) 2018 Sep;235(9):2479-2505.PMID:29980822DOI:10.1007/s00213-018-4921-9.
Rationale and objective: Two mechanisms underlie smoking cessation efficacies of α4β2* nicotinic acetylcholine receptor (nAChR) agonists: a "nicotine-like" agonist activity reduces craving by substituting for nicotine during a quit attempt, and a "nicotine-blocking" antagonist activity attenuates reinforcement by competing with inhaled nicotine during a relapse. To evaluate the contribution of each mechanism to clinical efficacy, we estimated the degree of agonist and antagonist activities of nicotine replacement therapy (NRT), varenicline, cytisine, and the discontinued nAChR agonists dianicline, ABT-418, ABT-089, CP-601927, and CP-601932, relative to the functional effects of nicotine from smoking. Methods: Functional activities that occur in vivo with clinical doses were predicted from literature data on binding and functional potencies at the target α4β2 nAChR, as well as at α6β2* nAChRs, and from estimates of free drug exposures in human brain. Agonist activity is comprised of nAChR activation and desensitization, which were expressed as percentages of desensitization and activation by nicotine from smoking. Antagonist activity was expressed as the reduction in nAChR occupancy by nicotine during smoking in the presence of an agonist. Results: Comparisons with odds ratios at end of treatment suggest that extensive α4β2 and α6β2* nAChR desensitization combined with α6β2* nAChR activation at similar levels as nicotine from smoking is associated with clinical efficacy (NRT, varenicline, cytisine, ABT-418). Effective competition with inhaled nicotine for α4β2 and α6β2* nAChRs further improves clinical efficacy (varenicline). Other discontinued nAChR agonists have lower agonist and antagonist activities at α4β2 nAChRs and are inactive or less efficacious than NRT (dianicline, ABT-089, CP-601927, CP-601932). Conclusion: Three pharmacological effects appear to be key factors underlying smoking cessation efficacy: the degree of activation of α6β2* nAChRs, desensitization of α4β2 and α6β2* nAChRs (agonist activity), and the reduction of nicotine occupancy at α4β2 and α6β2* nAChRs (antagonist activity). No single activity is dominant, and the level of smoking cessation efficacy depends on the profile of these activities achieved at clinical doses. While adequate agonist activity alone seems sufficient for a clinical effect (e.g., NRT, cytisine), clinical efficacy is improved with substantial competitive antagonism of α4β2 nAChRs, i.e., if the drug has a dual agonist-antagonist mechanism of action (e.g., varenicline).
Toxicity study in juvenile rats with the α4β2 nicotinic acetylcholine receptor partial agonist CP-601,927
Birth Defects Res B Dev Reprod Toxicol 2011 Aug;92(4):323-32.PMID:21594972DOI:10.1002/bdrb.20298.
Background: CP-601927 is a selective α(4) β(2) nicotinic acetylcholine receptor (nAChR) partial agonist. The objective of this study was to assess the potential effects persisting into adulthood when CP-601,927 was administered to neonatal/juvenile rats. Since the juvenile toxicity study was being performed early in the development program and this study would represent the longest dosing period yet evaluated, the study design incorporated standard endpoints typically evaluated in a general toxicity screening study. Methods: CP-601,927 was administered to Sprague-Dawley rats from postnatal day (PND) 7-70 by oral gavage at doses of 0.3, 1, or 3 mg/kg. During treatment animals were evaluated for growth, development, and sexual maturation. At the end of the treatment period general toxicity screening endpoints were collected (e.g., organ weights, histology, clinical chemistry). Following a 2-week latency period, animals were evaluated for CNS function in a comprehensive behavioral training battery consisting of a functional observational battery, motor activity, acoustic startle response, and learning and memory evaluations. Reproductive competency was evaluated by mating treated rats and allowing pregnant dams to deliver and rear their litters until PND 10. Results and conclusions: Treatment-related findings included the death of 2 males receiving 3 mg/kg CP-601,927, and transient reductions in body weight for both males and females during the third week of dosing which quickly recovered to control levels. The only treatment-related alteration in behavior was decreased motor activity, which occurred only in females at the highest dose tested. CP-601,927 had no effect on acoustic startle response, learning and memory, sexual maturation, reproductive capacity, or general toxicity endpoints.
Therapeutic doses of antidepressants are projected not to inhibit human α4β2 nicotinic acetylcholine receptors
Neuropharmacology 2013 Sep;72:88-95.PMID:23639435DOI:10.1016/j.neuropharm.2013.04.027.
Inhibition of central α4β2 nAChRs by antidepressants, proposed to contribute to their clinical efficacy, was assessed for monoamine reuptake inhibitors (amitriptyline, nortriptyline, fluoxetine, sertraline, paroxetine, citalopram) by comparing projected human unbound brain drug concentrations (Cu,b) at therapeutic doses with concentrations that inhibit human α4β2 nAChRs in vitro. Inhibitory concentrations (IC50) were determined by patch clamp and ranged from 0.8-3.2 μM, except for nortriptyline (IC50 = 100 nM). Cu,b values were calculated from human unbound plasma drug concentrations (Cu,p) and rat-derived brain-to-plasma and extracellular fluid-to-plasma ratios for the unbound drug, which are near unity, due to much higher brain tissue binding than plasma protein binding of these drugs. Accordingly in humans, antidepressant Cu,b are projected to essentially equal Cu,p, with average values from 3-87 nM, which are 30-to-250-fold below their IC50 concentrations. Based on our model, monoaminergic antidepressants minimally inhibit central nAChRs and it is unlikely that α4β2 nAChR antagonism contributes to their antidepressant activity. Nortriptyline is an exception with a Cu,b that is 2-fold below its IC50, which is comparable to the nAChR antagonist (±)-mecamylamine, for which Cu,b is 4-fold below its IC50; both drugs will inhibit a substantial fraction of α4β2 nAChRs. The Cu,b of the α4β2 nAChR partial agonist varenicline, which has antidepressant-like activity in a murine model, is higher than its IC50 and varenicline is projected to cause ~70% inhibition of α4β2 nAChRs. Taken together these data may help explain the negative outcome of recent antidepressant augmentation trials with mecamylamine and the partial agonist CP-601927.