CGP 35348

GABAB receptor (EC50 = 34 μM)

本文描述了新型GABAB受体阻断剂CGP 35348的生化、电生理和药理学特性。在多种受体结合试验中，CGP 35348仅显示出对GABAB受体的亲和力。CGP 35348对GABAB受体的IC50为34微M。该化合物拮抗了L-巴氯芬对去甲肾上腺素诱导的大鼠皮质切片腺苷酸环化酶刺激的增强作用（100、300、1000微M）。在电生理学研究中，CGP 35348（10100微M）拮抗了L-巴氯芬在离体大鼠脊髓中的作用。在海马切片制备中，CGP 35348（10、30、100微M）阻断了D/L-巴氯芬（10微M）诱导的膜超极化和晚期抑制性突触后电位。CGP 35348的效力似乎是GABAB受体阻断剂法氯芬的10-30倍。离子电泳和行为实验表明，腹腔注射CGP 35348后，大脑中的GABAB受体被阻断。该化合物在阐明脑GABAB受体的作用方面可能具有相当大的价值[1]。

CGP 35348 促进非快速眼动睡眠和快速眼动 (REM) 睡眠并降低高尖峰电流 [3]。

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为了研究CGP 35348对缺氧缺血损伤后白化小鼠学习记忆的影响，将10天大的白化小鼠进行右侧颈总动脉结扎，然后进行8%缺氧25分钟。脑损伤后，小鼠被喂食正常的啮齿动物饮食，直到13周大。此时，小鼠被分为两组。第1组接受生理盐水，第2组接受皮下注射CGP 35348（1mg/mL溶剂/Kg体重）12天。一系列用于评估长期神经功能的测试（Morris水迷宫、Rota棒和开放场）以及脑梗死测量。总体而言，CGP 35348改善了雄性和雌性白化小鼠的运动功能，但在雌性白化小鼠中效果更为明显。在野外，CGP 35348治疗的雌性白化小鼠表现出较差的探索行为。在Morris水迷宫试验中，观察到性别特异性效应，因为CGP 35348改善了雄性白化小鼠的空间学习和记忆以及游泳速度，但对缺氧缺血性脑病（HIE）后的雌性白化小鼠没有影响。我们得出结论，GABAB受体拮抗剂CGP 35348可用于改善基于性别的空间记忆。[2]

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GABAB拮抗剂CGP 35348以100、300和900mg/kg的剂量腹腔注射给老年大鼠。这些大鼠早期被长期提供EEG和EMG电极。注射后3小时，根据EEG和EMG记录的视觉检查进行睡眠记录，并额外观察记录笼中的自发行为。与注射生理盐水的对照组相比，100和300mg/kg的药物使REM睡眠的持续时间增加。REM睡眠潜伏期相应减少。非快速眼动睡眠和总睡眠时间增加，并发现了s形剂量反应关系。注射100和300mg/kg CGP 35348后，探索行为减弱。在所有剂量的CGP 35348后和所有3个记录小时内，尖峰波放电的数量和持续时间都减少了。后者的结果证实了该药物对尖峰波放电的强烈抑制作用；这些效应在失神癫痫模型中也有报道。考虑到促进REM睡眠的药物很少，服用CGP 35348后的催眠特性，特别是REM睡眠的增加值得关注。促进REM睡眠的药物的发现可能具有理论和临床意义[3]。

Animal/Disease Models: Eight male Wistar rats [3]
Doses: 100, 300 and 900 mg/kg
Route of Administration: intraperitoneal (ip) injection Results given: Compared with the control group injected with 100 and 300 mg/kg saline, rapid Eye movement sleep duration increased.

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Following weaning, mice were separated from their parents and fed on normal mouse diet until 13th week of life when they either received intraperitoneal injections of GABAB receptor antagonist CGP 35348 [(3-aminopropyl), (diethoxymethyl) phosphinic acid] at the rate of 1 mg/mL solvent/Kg body weight or saline solution for 12 days. CGP 35348 was dissolved in saline solution. [2]
Rotarod [2]
Balance and coordination in mouse was observed by using rotarod (locally manufactured) tests. It consists of a rotating drum. The drum rotated with 40 revolutions per minute. The time the animal spent on rotating drum was recorded. One pretraining trial was given to each animal. Three more consecutive trials were given to complete the experiment. The average time of these trials was obtained by using Sunyer et al.'s methods.

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Open Field (OF) [2]
A video camera attached with computational tracking system, Any-Maze, was used for observing the mice in a chamber which was 40 cm × 40 cm long and walls were 70 cm high. Ten-minute time was used for observation. For each trial the individual mouse was released in the center of the box. Distance covered, mean speed, maximum speed, time mobile, resting time, rotations, and freezing time were studied following Weitzdoerfer et al.

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Morris Water Maze (MWM) [2]
Mice were trained to swim towards platform which was hidden under the water 1.5 cm deep. By using compass North East, North West, South West, and South East locations were allocated to the pool which divided the pool into four quadrants. It was attached to computerised tracking/image analyzer system with computational tracking system Any-Maze. During the experiment the centre of the North East quadrant had the platform. 16 training trials were carried out on the mice for four days which is called spatial acquisition phase. Four training trials were taken daily and after each trial there was an interval of 15 minutes. They were allowed to search for platform for 2 minutes.The mice were kept on the platform by hand for 30 sec if they failed to find the platform after 2 min. At the end of acquisition phase, animal was tested for probe trial on the 5th day. Mice started swimming from the south start point. They were allowed maximum time of 60 sec to swim freely. After an interval of six days of the first trial of the retention phase mice received second probe trial for 60 sec. Mice were not given any trial between the 1st and 2nd probe trials according to Sunyer et al. [12]. The swimming pattern during acquisition phase was also recorded.

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Eight male Wistar rats, with body weights between 389 and 460 g and ages of about 24 months, were used. Animals lived under a 12- 12 LD cycle with white lights on at 2000 h. Red light was switched on during the dark period. Rats were implanted with a permanent tripolar EEG electrode set for recording the fronto- occipital EEG, and a bipolar electrode set for recording the nu- chal electromyogram (EMG). Rats were randomly assigned to one of four order groups of two subjects. All animals received saline, 100, 300, or 900 mg/kg CGP 35348 in four different sequences according to a Latin square design to control for order effects, so each rat received all three drug doses and the control injection. CGP 35348, solved in saline, was admin- istered IP at a volume of 2 ml/kg. The intersession interval was at least 48 h. Pharmacokinetic studies of CGP 35348 have not been performed in vivo; pharmacological data show that the EEG effects of CGP 35348 disappear in 2 to 3 h after administration. Al- though kinetics might be different in old subjects, it is not likely that it will largely exceed the half-live values of commonly used rats. Therefore, it seems safe to state that the drug effects are not likely due to the 48-h wash-out period. Moreover, in a Latin square design, order effects are counterbalanced. [3]

[1]. CGP 35348: a centrally active blocker of GABAB receptors. CGP 35348: a centrally active blocker of GABAB receptors.

[2]. CGP 35348, GABA B receptor antagonist, has a potential to improve neuromuscular coordination and spatial learning in albino mouse following neonatal brain damage. Biomed Res Int. 2014;2014:295215.

[3]. Effects of the GABAB antagonist CGP 35348 on sleep-wake states, behaviour, and spike-wave discharges in old rats. Brain Res Bull. 1996;40(3):157-62.

In summary, we used CGP 35348 to observe its effect on behavior and physiology of male and female albino mice following brain damage. We observed that overall CGP 35348 had improved the motor function in male and female albino mice but this treatment was more effective in females than in male albino mice. In open field test, female albino mice displayed poor exploratory and locomotory behavior following CGP 35348 supplementation. During Morris water maze test, we again observed the gender specific effects as CGP 35348 improves spatial learning and memory in male albino mice but had no effect on female albino mice following HIE indicating that CGP 35348 has a potential to improve neuromuscular coordination and spatial learning in male albino mice.[2]

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In conclusion, this paper reports that the GABA~ antagonist CGP 35348 enhances non-REM sleep and REM sleep and re- duces strongly spike-wave discharges. Both behavioural and EEG parameters contributed to the establishment of a hypnotic effect. The highest dose of CGP 35348 was not effective in pro- moting REM sleep. The REM-sleep-enhancing effects might have theoretical and clinical relevance.[3]

C8H20NO4P

225.2225

225.113

C, 42.66; H, 8.95; N, 6.22; O, 28.41; P, 13.75

123690-79-9

107699

Off-white to light yellow ointment

1.131g/cm3

400.5ºC at 760mmHg

196ºC

1.55E-07mmHg at 25°C

1.459

1.662

91.59

2

5

8

14

182

0

NCCCP(C(OCC)OCC)(=O)O

QIIVUOWTHWIXFO-UHFFFAOYSA-N

InChI=1S/C8H20NO4P/c1-3-12-8(13-4-2)14(10,11)7-5-6-9/h8H,3-7,9H2,1-2H3,(H,10,11)

3-aminopropyl(diethoxymethyl)phosphinic acid

Cgp 35348; 123690-79-9; Cgp-35348; CGP35348; 3-aminopropyl(diethoxymethyl)phosphinic acid; Phosphinic acid, P-(3-aminopropyl)-P-(diethoxymethyl)-; (3-aminopropyl)(diethoxymethyl)phosphinic acid; P-(3-Aminopropyl)-P-diethoxymethylphosphinic acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~83.33 mg/mL (~369.99 mM)

配方 1 中的溶解度: 25 mg/mL (111.00 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。