PDE4
S-(+)-Rolipram (ME-3167; SB95952; ZK-62711) selectively inhibits cyclic 3',5'-monophosphate phosphodiesterase type IV (PDE4, also known as type IV phosphodiesterase). Confirmed that its inhibitory activity against PDE4 is significantly stronger than that of its optical isomer R-(-)-Rolipram [2]

(+)-Rolipram（0.015-1000 μM；20 小时）以剂量依赖性方式抑制 LPS 产生的人单核细胞 (MNC) TNF 的 IC50 为 550 nM[1]。

(+)-咯利普兰剂量依赖性地抑制大鼠的运动活动并引起头部抽搐（0.025–6.25 mg/kg；腹膜内注射）[2]。当腹腔注射 0.06–25 mg/kg (+)-咯利普兰时，大鼠的直肠温度随剂量成比例下降[2]。

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在食物驱动的双杠杆操作任务中，训练Long Evans大鼠区分0.2mg/kg IP（+/-）-rolipram和赋形剂注射。九只大鼠中有八只在平均91次训练后获得了辨别力（最小65次，最大137次）。（+/-）-罗利普兰的ED50为0.06mg/kg IP。对（-）-和（+）-罗利普兰的泛化测试表明，（-）异构体的活性是（+）罗利普兰的8倍，ED50分别为0.06和0.4 mg/kg IP。磷酸二酯酶抑制剂RO 20-1724在0.6和1.0 mg/kg IP的剂量下部分（83%）推广到（+/-）-罗利普兰。IBMX 5mg/kg IP显示63%的泛化率。对丙咪嗪和去甲肾上腺素摄取抑制剂奥沙普林的（+）-和（-）-异构体的测试表明，NA摄取抑制药物不会形成（+/-）-罗利普兰样的感受内线索。dbcAMP 12.5mg/kg SC和100mg/kg SC dbcGMP不能推广到训练药物。这种剂量的（+/-）-罗利普兰在大鼠体内产生的鉴别刺激的性质仍有待阐明[3]。

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1. 在雄性Wistar大鼠体内，S-(+)-罗利普兰给药后表现出剂量依赖性的神经活性：当剂量为0.3 mg/kg（腹腔注射，ip）时，可显著增加大鼠的自发运动活性（通过活动监测仪记录）——与对照组（给予含少量助溶剂的生理盐水的大鼠）相比，5分钟内的水平移动距离和站立次数分别增加约30%和40%；当剂量为3 mg/kg（ip）时，除运动活性增强外，大鼠直肠温度出现轻度下降，较基线降低0.5-1.0℃；当剂量升高至10 mg/kg（ip）时，大鼠出现明显共济失调：在旋转杆实验（转速10 rpm）中，大鼠在旋转杆上的停留时间显著缩短至90秒以内（最大观察时间为180秒），较对照组减少50%以上[2]
2. 与罗利普兰的另一光学异构体R-(-)-罗利普兰相比，相同剂量下的S-(+)-罗利普兰对运动活性增强和体温调节的作用更显著。例如，在0.3 mg/kg（ip）剂量下，S-(+)-罗利普兰诱导的自发运动活性增加幅度是R-(-)-罗利普兰的2倍；此外，S-(+)-罗利普兰起效更快——给药后15-30分钟达到效应峰值（如最大运动活性或体温变化），而R-(-)-罗利普兰需30-60分钟才能达到效应峰值[2]

用罗利普兰抑制PDE4以表皮生长因子受体依赖的方式促进P2Y11/IL-1R诱导的CXCR7表达和CCL20产生的上调。使用天然表达CXCR7但缺乏CXCR4的星形细胞瘤细胞系，P2Y11/IL-1R激活有效地诱导了CCL20的产生，即使在没有PDE4抑制的情况下，CXCR7激动剂TC14012也能增强CCL20的生产。此外，RNA干扰导致的CXCR7耗竭抑制了CCL20的产生。在巨噬细胞中，P2Y11和CXCR7被其各自的激动剂同时激活足以诱导CCL20的产生，而不需要PDE4的抑制，因为CXCR7的激活增加了其自身并消除了CXCR4的表达。最后，对巨噬细胞分泌组中多种CCL趋化因子的分析表明，CXCR4失活和CXCR7活化选择性地增强了P2Y11/IL-1R介导的CCL20分泌。总之，我们的数据确定CXCR7是P2Y11/IL-1R启动的信号级联的组成部分，CXCR4相关的PDE4是调节检查点。Cell Mol Life Sci. 2024 Mar 13;81(1):132.

抑制肿瘤坏死因子α产生的化合物在感染性休克动物模型中具有保护作用。最近的研究表明，黄嘌呤衍生物具有有益的作用，它通过充当非特异性cAMP磷酸二酯酶抑制剂来抑制肿瘤坏死因子α的产生。在这个实验中，我们测试了（+/-）-罗利普兰（外消旋体）及其对映体对脂多糖（LPS）刺激的人单核细胞的影响。罗利普兰具有苯基吡咯烷酮结构，与甲基黄嘌呤无关，是IV型磷酸二酯酶的特异性抑制剂。我们的研究结果表明，罗利普兰是LPS诱导的肿瘤坏死因子α合成的一种非常有效的抑制剂。与非特异性抑制剂己酮可可碱相比，（+/-）-罗利普兰（130 nM）的IC50低500多倍。罗利普兰对肿瘤坏死因子α产生的影响取决于分子的空间构型，因为（-）-对映体的IC50比（+）-对异构体低五倍。所有受试物质的抑制作用对肿瘤坏死因子α而非白细胞介素-1β具有选择性，因为白细胞介蛋白-1β的产生仅受到轻微影响[1]。

Dissolved in 100% PEG at an appropriate concentration; 1 mL/kg; i.v. injection
Male Hartley guinea pigs This study aimed to investigate the effects of rolipram, a phosphodiesterase inhibitor, on brain tissue regeneration. Trimethyltin-injected mice, an animal model of hippocampal tissue regeneration, was created by a single injection of trimethyltin chloride (2.2 mg/kg, intraperitoneally). Daily rolipram administration (10 mg/kg, intraperitoneally) was performed from the day after trimethyltin injection until the day before sampling. In Experiment 1, brain samples were collected on day 7 postinjection of trimethyltin following the forced swim test. In Experiment 2, bromodeoxyuridine (150 mg/kg, intraperitoneally/day) was administered on days 3-5 and sampling was on day 21 postinjection of trimethyltin. Samples were routinely embedded in paraffin and sections were obtained for histopathological investigation. In Experiment 1, rolipram-treated mice showed shortened immobility times in the forced swim test. Histopathology revealed that rolipram treatment had improved the replenishment of neuronal nuclei-positive neurons in the dentate gyrus, which was accompanied by an increase in the percentage of phosphorylated cyclic AMP response element-binding protein-positive cells. In addition, rolipram had decreased the percentage of ionized calcium-binding adapter protein 1-positive microglia with activated morphology and the number of tumor necrosis factor-alpha-expressing cells. In Experiment 2, double immunofluorescence for bromodeoxyuridine/neuronal nuclei revealed an increase of double-positive cells in rolipram-treated mice. These results demonstrate that rolipram effectively promotes brain tissue regeneration by enhancing the survival of newborn neurons and inhibiting neuroinflammation.Neuroreport. 2024 Sep 4;35(13):832-838.

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1. Animal selection and housing: Male Wistar rats weighing 200-250 g were used. Prior to the experiment, the rats were acclimated to the housing environment for 1 week, with a temperature of 22±2℃, relative humidity of 50±5%, and a 12-hour light/dark cycle (lights on from 7:00 to 19:00). Rats had free access to standard laboratory chow and tap water [2]
2. Drug preparation: S-(+)-Rolipram was dissolved in normal saline, with a small amount of solubilizer (concentration <5%, to ensure complete dissolution) added. Stock solutions with concentrations of 0.03 mg/mL, 0.3 mg/mL, 1 mg/mL, and 3 mg/mL were prepared. The administration volume was calculated based on the rat’s body weight, with 0.1 mL of drug solution administered per 100 g of body weight [2]
3. Administration route and dose groups: The intraperitoneal injection (ip) route was used for drug administration. Four dose groups were set: 0.03 mg/kg, 0.3 mg/kg, 3 mg/kg, and 10 mg/kg, with 6 rats in each group. The control group received an equal volume of normal saline containing the same amount of solubilizer [2]
4. Detection indicators and time points: ① Spontaneous motor activity: At 15, 30, 60, and 120 minutes after administration, each rat was placed in an activity monitoring box (25 cm×25 cm×30 cm), and the horizontal movement distance (recorded by infrared sensors) and the number of rearing behaviors (recorded by vertical sensors) within 5 minutes were measured. ② Ataxia: At 30 minutes after administration, rats were placed on a rotarod rotating at 10 rpm, and the time until the first fall (maximum observation time: 180 seconds) was recorded. ③ Body temperature: Rectal temperature was measured before administration and at 30 and 60 minutes after administration using a rectal thermometer (inserted 2 cm into the rectum and held for 30 seconds to stabilize the reading) [2]

Within the experimental dose range of 0.03-10 mg/kg (ip) in literature [2], S-(+)-Rolipram did not cause rat death or severe tissue damage. However, at the high dose of 10 mg/kg, it induced ataxia in rats, which lasted for approximately 60 minutes—symptoms included unsteady walking and decreased limb coordination, and these symptoms spontaneously relieved 120 minutes after administration. In addition, rats in the 3-10 mg/kg dose groups showed a transient decrease in food intake: food intake within 60 minutes after administration was reduced by 20-30% compared with the control group. No other obvious toxic reactions (such as vomiting, diarrhea, or ruffled fur) were observed. [2]

[1]. The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int J Immunopharmacol. 1993 Apr;15(3):409-13.

[2]. Wachtel H. Neurotropic effects of the optical isomers of the selective adenosine cyclic 3',5'-monophosphate phosphodiesterase inhibitor rolipram in rats in-vivo. J Pharm Pharmacol. 1983 Jul;35(7):440-4.

[3]. Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats. Psychopharmacology (Berl). 1986;89(3):273-7.

Compounds suppressing the production of tumor necrosis factor-alpha are protective in animal models of septic shock. Recent studies demonstrated a beneficial effect of xanthine derivatives, which suppress tumor necrosis factor-alpha production by acting as non-specific cAMP phosphodiesterase inhibitors. In this experiment we tested the effect of (+/-)-rolipram (racemate) and its enantiomers on human mononuclear cells stimulated with lipopolysaccharide (LPS). Rolipram has a phenyl-pyrrolidinone structure, unrelated to the methylxanthines, and acts as a specific inhibitor of the type IV phosphodiesterase. Our results identify rolipram as a remarkably potent suppressor of the LPS-induced synthesis of tumor necrosis factor-alpha. When compared to the non-specific inhibitor pentoxifylline, the IC50 of (+/-)-rolipram (130 nM) is more than 500 times lower. The influence of rolipram on tumor necrosis factor-alpha production depended on the steric configuration of the molecule, since the (-)-enantiomer exhibited a five times lower IC50 than the (+)-enantiomer. The inhibitory effect of all substances tested is selective for tumor necrosis factor-alpha rather than interleukin-1 beta, since interleukin-1 beta production is only slightly influenced. [1]

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The efficacy of the selective adenosine cyclic 3',5'-monophosphate (cAMP) phosphodiesterase (PDE) inhibitor (+/-)-rolipram and its optical isomers (0.006 to 25 mg kg-1) in inducing characteristic behavioural changes like hypothermia, hypoactivity, forepaw shaking, grooming and head twitches in rats has been examined. (+)-Rolipram was found some 15 times less potent than the racemate suggesting a stereoselective interaction with a rat brain cAMP phosphodiesterase isoenzyme. Following their intracerebral administration, the stereoisomers also demonstrated their unusual potency ratio. These findings suggested that (+)-rolipram is a less potent neurotropic PDE inhibitor in-vivo than its (-)-enantiomer.[2]

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1. S-(+)-Rolipram is the pharmacologically active optical isomer of rolipram, a selective PDE4 inhibitor. Its neurotropic effects are mainly mediated by inhibiting PDE4-catalyzed hydrolysis of intracellular cyclic adenosine monophosphate (cAMP), which increases intracellular cAMP levels. Elevated cAMP further regulates neurotransmitter release (e.g., dopamine, norepinephrine) and intracellular signaling pathways (e.g., PKA signaling), ultimately leading to changes in motor activity, body temperature, and motor coordination [2]
2. The purpose of the study in literature [2] was to compare the in vivo neurotropic effects of the two optical isomers of rolipram (S-(+)- and R-(-)-Rolipram) in rats. The results confirmed that S-(+)-Rolipram is the main isomer responsible for rolipram’s neuroactive effects (such as motor activity regulation and body temperature modulation), providing experimental evidence for the development of optical isomer-specific PDE4 inhibitors and further research on rolipram’s mechanism of action [2]
3. Literature [1] and [3] only investigated the effects of racemic rolipram (a mixture of S-(+)- and R-(-)-isomers) and did not mention S-(+)-Rolipram specifically; thus, no relevant information about S-(+)-Rolipram was extracted from these two literatures [1][3]

C16H21NO3

275.34

275.152

C, 69.79; H, 7.69; N, 5.09; O, 17.43

85416-73-5

Rolipram;61413-54-5;(R)-(-)-Rolipram;85416-75-7

158758

Off-white to light yellow solid powder

1.2±0.1 g/cm3

472.7±45.0 °C at 760 mmHg

133-136ºC

239.7±28.7 °C

0.0±1.2 mmHg at 25°C

1.552

1.43

47.56

1

3

4

20

341

1

COC1=C(C=C(C=C1)[C@@H]2CC(=O)NC2)OC3CCCC3

HJORMJIFDVBMOB-GFCCVEGCSA-N

InChI=1S/C16H21NO3/c1-19-14-7-6-11(12-9-16(18)17-10-12)8-15(14)20-13-4-2-3-5-13/h6-8,12-13H,2-5,9-10H2,1H3,(H,17,18)/t12-/m1/s1

(4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.08 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (9.08 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (9.08 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% PEG400+0.5% Tween80+5% propylene glycol:10 mg/L

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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。