5-HT_4A Receptor ( pKi = 8.6 ); 5-HT_4B Receptor ( pKi = 8.1 )

体外活性：普芦卡必利以浓度依赖性方式诱导收缩，pEC50 为 7.5。 Prucalopride (1 mM) 显着放大电场刺激后豚鼠近端结肠的回弹收缩。普卢卡必利诱导大鼠食管粘膜肌层松弛，pEC50 为 7.8，产生单相浓度-反应曲线。激酶测定：普芦卡必利是一种新型肠动力化合物，是苯并呋喃类的第一个代表。我们着手在各种受体结合和器官浴实验中建立其药理学特征。受体结合数据表明普卡必利对所研究的两种 5-HT(4) 受体亚型具有高亲和力，人 5-HT(4a) 和 5-HT(4b) 受体的平均 pK(i) 估计值分别为 8.60 和 8.10 。在本研究中研究的 50 种其他结合测定中，仅人类 D(4) 受体 (pK(i) 5.63)、小鼠 5-HT(3) 受体 (pK(i) 5.41) 和人类 sigma(1)（ pK(i) 5.43) 显示出可测量的亲和力，导致对 5-HT(4) 受体的选择性至少为 290 倍。经典的器官浴实验是使用来自大鼠、豚鼠和狗胃肠道的分离组织，采用各种方案进行的。普芦卡必利是豚鼠结肠中的 5-HT(4) 受体激动剂，因为它诱导收缩 (pEC(50)=7.48+/-0.06；对 5-HT(2A) 或 5-HT(3) 不敏感受体拮抗剂，但被 5-HT(4) 受体拮抗剂抑制）以及促进电刺激诱导的非胆碱能收缩（被 5-HT(4) 受体拮抗剂阻断）。此外，它以5-HT(4)受体拮抗剂敏感的方式引起大鼠食道制剂的松弛(pEC(50)＝7.81+/-0.17)。普芦卡必利不会引起 5-HT(2A)、5-HT(2B) 或 5-HT(3)、胃动素或胆囊收缩素 (CCK(1)) 受体介导的收缩的相关抑制，也不会引起烟碱或毒蕈碱乙酰胆碱受体的相关抑制。介导的收缩，高达 10 microM。结论是普卡必利是一种有效的、选择性的、特异性的5-HT(4)受体激动剂。由于其用于治疗肠道动力障碍，因此需要注意的是，普卡必利缺乏抗胆碱能、抗胆碱酯酶或非特异性抑制活性，并且不拮抗 5-HT(2A)、5-HT(2B) 和 5-HT(2A)、5-HT(2B) 和 5-HT(2B)。 HT(3) 受体或胃动素或CCK(1) 受体。细胞测定：经典的器官浴实验是使用来自大鼠、豚鼠和狗胃肠道的分离组织，使用各种方案进行的。普芦卡必利是豚鼠结肠中的 5-HT(4) 受体激动剂，因为它诱导收缩 (pEC(50)=7.48+/-0.06；对 5-HT(2A) 或 5-HT(3) 不敏感受体拮抗剂，但被 5-HT(4) 受体拮抗剂抑制）以及促进电刺激诱导的非胆碱能收缩（被 5-HT(4) 受体拮抗剂阻断）。此外，它以5-HT(4)受体拮抗剂敏感的方式引起大鼠食道制剂的松弛(pEC(50)＝7.81+/-0.17)。

接受 2 mg 普芦卡必利治疗组的每周完全排便率为 30.9%，接受 4 mg 普芦卡必利治疗组的患者为 28.4%，而安慰剂组为 12.0%。接受 2 mg 普芦卡必利治疗的患者中，有 47.3% 的患者和接受 4 mg 普芦卡必利治疗的患者中，平均每周自发、完全排便次数增加了 1 次或多次，而安慰剂组中这一比例为 25.8%。 。普芦卡必利（2 mg 或 4 mg）显着改善所有其他次要疗效终点，包括患者对肠道功能和治疗的满意度以及对便秘症状严重程度的感知。普芦卡必利（每日 4 毫克）可加速无直肠排便障碍的便秘患者的整体胃排空和小肠转运。普芦卡必利（每日 4 毫克）往往会加速整体结肠转运，显着加快整体结肠转运和升结肠排空。与安慰剂组 (9.6%) 相比，服用普卡必利 2 mg (19.5%)、4 mg (23.6%) 的患者每周有 3 次或更多自发性完全排便 (SCBM) 的比例较高。普芦卡必利还显着改善次要疗效和生活质量终点，包括每周一次或多次 SCBM 增加的患者比例、疏散完整性、感知疾病严重程度以及治疗效果和生活质量。普卢卡必利通过刺激近端结肠的高幅度集群收缩和抑制禁食狗远端结肠的收缩活动，以剂量依赖的方式改变结肠收缩运动模式。普芦卡必利还会导致第一次巨大迁移性收缩 (GMC) 时间出现剂量依赖性缩短；使用较高剂量的普卡必利时，第一次 GMC 通常发生在治疗后的前半小时内。

普芦卡必利是苯并呋喃类的第一个成员，也是一种新型肠动力化合物。我们的目标是通过一系列器官浴和受体结合实验来确定其药理学特征。人类 5-HT(4a) 和 5-HT(4b) 受体的平均 pK(i) 估计值分别为 8.60 和 8.10，受体结合数据表明普卡必利对所研究的两种 5-HT(4) 受体亚型具有高亲和力。仅人类 D(4) 受体 (pK(i) 5.63)、小鼠 5-HT(3) 受体 (pK(i) 5.41) 和人类 sigma(1) (pK(i) 5.43) 表现出可测量的亲和力从本研究中检查的 50 种其他结合测定中得出，对 5-HT(4) 受体的选择性至少是 290 倍。使用不同的方案对大鼠、豚鼠和狗的分离胃肠道组织进行经典器官浴实验。在豚鼠结肠中，普卡必利是 5-HT(4) 受体激动剂，因为它引起收缩 (pEC(50)=7.48+/-0.06；对 5-HT(2A) 或 5-HT(3) 不敏感受体拮抗剂，但被 5-HT(4) 受体拮抗剂抑制）并促进电刺激诱导的非胆碱能收缩（被 5-HT(4) 受体拮抗剂阻断）。此外，它还导致大鼠食道制剂对5-HT(4)受体拮抗剂敏感的松弛(pEC(50)=7.81+/-0.17)。高达 10 µM 的普拉昔卡必利不会显着抑制由 5-HT(2A)、5-HT(2B) 或 5-HT(3) 受体、胃动素或胆囊收缩素 (CCK(1)) 受体介导的收缩，或烟碱或毒蕈碱乙酰胆碱受体。总之，普卡必利是一种强效、特异性、选择性的5-HT(4)受体激动剂。值得注意的是，普卡必利不会阻碍 5-HT(2A)、5-HT(2B) 和 5-HT(3) 受体、胃动素或 CCK(1) 受体的作用，并且不是抗胆碱能、抗胆碱酯酶或非特异性抑制活性。这很重要，因为该药物旨在治疗与肠道蠕动相关的疾病。

使用不同的方案对大鼠、豚鼠和狗的分离胃肠道组织进行经典器官浴实验。在豚鼠结肠中，普卡必利是 5-HT(4) 受体激动剂，因为它引起收缩 (pEC(50)=7.48+/-0.06；对 5-HT(2A) 或 5-HT(3) 不敏感受体拮抗剂，但被 5-HT(4) 受体拮抗剂抑制）并促进电刺激诱导的非胆碱能收缩（被 5-HT(4) 受体拮抗剂阻断）。此外，它还导致大鼠食道制剂对5-HT(4)受体拮抗剂敏感的松弛(pEC(50)=7.81+/-0.17)。

Sprague dawley rats (diabetes mellitus (DM) model)
5 or 10 µg/kg
Oral gavage; single daily for 2 weeks.

Absorption, Distribution and Excretion
Prucalopride is well absorbed and it reaches maximum plasma concentration of 3.79ng/ml with a tmax of 2.77 hours after initial administration. It presents an AUC of 96.5 mn.h/ml. The bioavailability of prucalopride is of over 90% and this bioavailability does not get influenced by the ingestion of food.
After maximum plasma concentration, prucalopride concentration decline in a biphasic manner. Prucalopride is mainly excreted by the urine, representing 84% of the administered dose while only 13% of the dose is recovered in feces.
The mean volume of distribution of prucalopride is registered to be 623 L.
Prucalopride renal clearance is reported to be of 17 L/h which actually exceeds the glomerular filtration rate of the kidney.

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Metabolism / Metabolites
Prucalopride is not extensively metabolized in the body and does not interact with the enzymes of the family of the cytochrome P450 enzymes nor the P glycoprotein. The metabolism of prucalopride only represents 6% of the administered dose and the remaining 94% is found as the unchanged drug. From studies, it was reported the recovery of 8 metabolites being the major metabolite R107504 which is formed after the O-demethylation and oxidation of the resulting alcohol to a carboxylic acid.

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Biological Half-Life
The reported half-life of prucalopride is of around 18-20 hours.

Hepatotoxicity
Prucalopride therapy was associated with a low rate of serum enzyme elevations during therapy (
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published experience exists with prucalopride during breastfeeding. However, the manufacturer reports an unpublished study that indicates a relatively low amount of drug in breastmilk. Until more data become available, monitor the breastfed infant for diarrhea.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is prucalopride?
Prucalopride is a medication used to treat adults with functional constipation, also known as chronic idiopathic constipation. Here, chronic means that symptoms, such as hard, infrequent bowel movements, have been happening for at least 6 months. Idiopathic means that the cause is not known. Prucalopride is sold under the brand name Motegrity®.Other forms of constipation might respond to over-the-counter (OTC) laxatives. For more information about OTC laxatives, please see the general laxatives MotherToBaby fact sheet at https://mothertobaby.org/fact-sheets/laxatives/.Sometimes when people find out they are pregnant, they think about changing how they take their medication or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take prucalopride. Can it make it harder for me to get pregnant?
Studies have not been done to see if prucalopride could make it harder to get pregnant.
◈ Does taking prucalopride increase the chance for miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. It is not known if prucalopride increases the chance of miscarriage,
◈ Does taking prucalopride increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. It is not known if prucalopride increases the chance for birth defects above the background risk. Human studies have not been done to see if prucalopride increases the chance for birth defects.  Animal studies done by the manufacturer did not show an increase in birth defects with exposure to prucalopride.
◈ Does taking prucalopride in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if prucalopride increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight(weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ Does taking prucalopride in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if prucalopride can cause behavior or learning issues for the child.
◈ Breastfeeding while taking prucalopride:
There are no published studies looking at the use of prucalopride during breastfeeding. The manufacturer reports an unpublished study that indicates a relatively low amount of prucalopride is passed into breast milk. If you suspect the baby has any symptoms (such as diarrhea), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes prucalopride, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if prucalopride could affect male fertility or increase the chance of birth defects. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
The plasma protein binding of prucalopride is of 30%.

[1]. Eur J Pharmacol . 2001 Jun 29;423(1):71-83.

[2]. N Engl J Med . 2008 May 29;358(22):2344-54.

[3]. Gastroenterology . 2001 Feb;120(2):354-60.

[4]. Gut. 2009 Mar;58(3):357-65.

[5]. Neurogastroenterol Motil . 2001 Oct;13(5):465-72.

Prucalopride is a member of benzamides.
Prucalopride is a dihydrobenzofurancarboxamide derivative from the benzofurane family that selectively stimulates 5-HT4 receptors and thus, it presents enterokinetic properties. The high selectivity of prucalopride allowed further development as it prevented the cardiac adverse reactions observed due to non-target effects of precedent therapies. Prucalopride was developed by Shire Development LLC and approved for use in Europe in 2009, in Canada on December 7, 2011 and by the FDA on December 17, 2018.
Prucalopride is a Serotonin-4 Receptor Agonist. The mechanism of action of prucalopride is as a Serotonin 4 Receptor Agonist.
Prucalopride is a serotonin type 4 (5-HT4) receptor agonist that has potent prokinetic activity and is used as therapy for chronic idiopathic constipation. Prucalopride has been associated with a minimal rate of transient serum enzyme elevations during therapy and has not been implicated in cases of clinically apparent liver injury with jaundice.
Prucalopride is an orally bioavailable dihydro-benzofuran-carboxamide and selective serotonin (5-HT4) receptor agonist, with gastrointestinal (GI) prokinetic activity. Upon oral administration, prucalopride specifically targets, binds to and stimulates the 5-HT4 receptor. This alters colonic motility patterns and stimulates colonic mass movements. This may normalize bowel movements and may relief chronic constipation. In addition, by increasing esophageal and gastric motility, prucalopride may also provide relief for aspiration-associated symptoms.
See also: Prucalopride Succinate (active moiety of); Prucalopride hydrochloride (is active moiety of).

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Drug Indication
Prucalopride is indicated for the treatment of chronic idiopathic constipation (CIC) in adults. CIC is one of the most common chronic functional gastrointestinal disorders worldwide. The diagnosis of this agent is very hard and it can be confirmed if the patient experience at least two of the following: -Straining during more than 25% of the bowel movements. -Lumpy or hard stools in 25% of the bowel movements. -Sensation of incomplete evacuation in more than 25% of all bowel movements. -Sensation of anorectal blockage or obstruction in more than 25% of the bowel movements. -Manual maneuvers required in more than 25% of the bowel movements. -Fewer than 3 bowel movements per week.
FDA Label
Resolor is indicated for symptomatic treatment of chronic constipation in adults in whom laxatives fail to provide adequate relief.

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Mechanism of Action
Prucalopride acts as a selective stimulator of the 5-HT4 receptors while having no interaction with hERG channel or 5-HT1 receptors which reduces significantly the cardiovascular risk found in other similar drugs. 5-HT4 receptors can be found throughout the gastrointestinal tract primarily in smooth muscle cells, enterochromaffin cells, and myenteric plexus. Its activation produces the release of acetylcholine which is the major excitatory neurotransmitter in the GI tract. Hence, prucalopride stimulates motility by interacting specifically with 5-HT4 receptors in the GI tract which causes a release of acetylcholine and further contraction of the muscle layer of the colon and relaxation of the circular muscle layer leading to the propulsion of luminal content.

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Pharmacodynamics
In animal studies, prucalopride induced a dose-dependent stimulation of contractile activity in the proximal colon and inhibition of the contractility in the distal colon. As well it has been shown that prucalopride stimulates and amplifies giant migratory contraction which is the high-amplitude type of contraction that initiates the urge to defecate. Thus, prucalopride not only accelerates the colonic transit but also accelerates gastric emptying and small bowel transit. In supratherapeutic concentrations, prucalopride can be observed to interact with hERG potassium channels and L-type calcium channels. In clinical trials, prucalopride showed to significantly increase the spontaneous bowel movements with a standardized mean difference of about 0.5 after the use of 1 mg when compared with the placebo group. In this studies as well, it was observed a numerical improvement in mean colonic transit time and a significant increase in spontaneous complete bowel movement without marked changes in the anorectal function. In phase III clinical trials, 86% of the tested individuals opted to continue with the open-label study and based on Patients Assessments, 67% of the patients increase more than one point improvement in their satisfaction. In the final set of clinical trials for approval, there was a significant increase in the number of patients that reached over 3 complete spontaneous bowel movements per week when compared with the placebo.

C18H26CLN3O3

367.87

367.166

C, 58.77; H, 7.12; Cl, 9.64; N, 11.42; O, 13.05

179474-81-8

Prucalopride succinate; 179474-85-2; Prucalopride-13C,d3; 2140306-00-7; Prucalopride hydrochloride; 179474-80-7; 179474-85-2 (Succinate)

3052762

White to off-white solid powder

1.3±0.1 g/cm3

481.4±45.0 °C at 760 mmHg

90.7°

244.9±28.7 °C

0.0±1.2 mmHg at 25°C

1.599

1.44

76.82

2

5

6

25

445

0

ClC1=C(C2C([H])([H])C([H])([H])OC=2C(=C1[H])C(N([H])C1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])OC([H])([H])[H])C([H])([H])C1([H])[H])=O)N([H])[H]

ZPMNHBXQOOVQJL-UHFFFAOYSA-N

InChI=1S/C18H26ClN3O3/c1-24-9-2-6-22-7-3-12(4-8-22)21-18(23)14-11-15(19)16(20)13-5-10-25-17(13)14/h11-12H,2-10,20H2,1H3,(H,21,23)

4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide

Prucalopride free base; R 093877; R-093877; R093877; R-108512; R 108512; R108512; R-93877; R93877； Prucalopride; Motegrity; Resolor; Resotran; R 93877

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: 50 mg/mL (135.92 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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配方 2 中的溶解度: ClC1=C(N)C(CCO2)=C2C(C(NC3CCN(CCCOC)CC3)=O)=C1

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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。