5-HT4 receptor ( EC50 = 140 nM ); hERG channel ( IC50 = 9.4 nM )

Cisapride is an agonist of the 5-HT4 receptor and an hERG blocker[1]. It is frequently used to treat disorders of gastrointestinal motility, including gastroparesis, slow-transit constipation, and chronic intestinal pseudo-obstruction, or gastroesophageal reflux disease (GERD). Through its ability to stimulate intestinal acetylcholine release from muscarinic receptors, cisapride works to promote motility of the gastrointestinal tract. Cisapride blocks the current in ventricular myocytes' L-type Ca2+ channels and the Kv 4.3 channels that are consistently expressed in Chinese hamster ovary (CEO) cells. In a concentration-dependent manner, cisapride inhibited Kv channel current without affecting its ability to act as a selective agonist of the serotonin 5-HT4 receptor[2].

Cisapride (0.1-1 mg/kg; injection, once) stimulates antral and aqueous motility in conscious dogs [3]. Endpoints of cisapride (2 mg/kg, (ip); 4 mg/kg, (oral); once) versus trinitrobenzene sulfonic acid treatment endpoints in terms of macroscopic features, histopathological features, cytokine profiles, and body weight changes There is no significant difference [4]. Animal model: Rat colitis induced by trinitrobenzene sulfonic acid (TNBS) in male Wistar rats [4] Dosage: 2 mg/kg (intraperitoneal injection); 4 mg/kg (orally) Administration method: 2 mg/kg, intraperitoneal injection; 4 mg/kg, oral administration; Results: Colitis rats developed severe and intense transmural inflammation and diffuse necrosis, inflammatory granuloma and submucosal neutrophil infiltration. Cause weight loss.

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There is a pressing need for research that will lead to the reveal of targets designed to analyse the possible pathways for the treatment of IBD. Because of the probable involvement of serotonin in inflammatory conditions of intestine and the important role of 5HT(4) receptors in GI function, the investigation of the role of 5HT(4) receptors in the pathogenesis of IBD will be interesting. The aim of this study was to investigate the effects of cisapride, a 5HT(4) receptor agonist, in trinitrobenzenesulfonic-acid-(TNBS) induced rat colitis. Two hours subsequent to induction of colitis using TNBS in rats, cisapride (2 mg/kg, intraperitoneally (i.p); 4 mg/kg, orally (p.o)) and dexamethasone (1 mg/kg, i.p; 2 mg/kg, p.o) were administrated for 6 days. Animals were thereafter euthanized; macroscopic, histological, and biochemical assessments and ELISA test were carried out on distal colon samples. Our data showed that dexamethasone treatment (i.p, p.o) significantly decreased macroscopic and microscopic damage and also biochemical markers, but there were no significant differences in aforementioned parameters between cisapride (i.p or p.o) and TNBS-treated rats. It can be deduced that because the severity of colitis produced by TNBS is massive (through various pathways), cisapride could not bring about more colitis damages through 5HT(4) receptors. Based on the present study further researches are required for investigating the exact roles of 5HT(4) receptors in the pathogenesis of ulcerative colitis.[4]

Mosapride and cisapride are gastroprokinetic agents with 5-hydroxytryptamine4 receptor agonist activity and have been widely used in the treatment of a variety of gastrointestinal disorders. The effects of mosapride and cisapride on cloned Kv4.3 channels stably expressed in Chinese hamster ovary cells were investigated using the whole-cell patch-clamp technique. Mosapride and cisapride inhibited Kv4.3 in a concentration-dependent manner with IC50 values of 15.2 and 9.8 μM, respectively. Mosapride accelerated the rate of inactivation and activation of Kv4.3 in a concentration-dependent manner and thereby decreased the time to peak. The rate constants of association (k +1) and dissociation (k -1) for mosapride were 9.9 μM(-1) s(-1) and 151.3 s(-1), respectively. The K D (k -1/k +1) was 16.2 μM, similar to the IC50 value calculated from the concentration-response curve. Voltage-dependent inhibition by mosapride was observed in the voltage range for channel opening but was not observed over a voltage range in which all Kv4.3 channels were open. Both the steady-state activation and inactivation curves of Kv4.3 were shifted in the hyperpolarizing direction in the presence of mosapride. Mosapride also caused a substantial acceleration in closed-state inactivation of Kv4.3. Mosapride produced use-dependent inhibition, which was consistent with a slow recovery from inactivation of Kv4.3. M1 and norcisapride, the major metabolites of mosapride and cisapride, respectively, had little or no effect on Kv4.3. These results indicate that mosapride inhibits Kv4.3 by both preferential binding to the open state of the channels during depolarization and acceleration of the closed-state inactivation at subthreshold potentials[2].

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In the receptor binding studies, mosapride inhibited [3H]-GR113808 binding to 5-HT4 receptor sites of guinea pig striatum with an IC50 value of 113 nM [3].

The blocking effect of three 5-HT(4) agonists, cisapride, mosapride, and the newly discovered CJ-033466 on the human ether-a-go-go-related gene (hERG) channel was studied using a whole cell patch-clamp technique in HEK293 cells. Cisapride was found to be the most potent of the hERG blockers. CJ-033466 had the widest safety margin between its hERG blocking activity and 5-HT(4) agonism among the tested compounds. This suggests a lower clinical risk of cardiac arrhythmia in CJ-033466 compared with the other 2 agonists. Therefore, CJ-033466 has the potential to be a drug with higher therapeutic efficacy and less cardiac risk than both cisapride and mosapride[1].

Male Wistar rats with trinitrobenzenesulfonic-acid-(TNBS) induced rat colitis
2 mg/kg (i.p.); 4 mg/kg, (oral administration)
2 mg/kg, intraperitoneal injection ; 4 mg/kg, oral administration; once

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Mosapride citrate is a new gastroprokinetic agent that enhances the upper GI motility by stimulating 5-hydroxytryptamine4 (5-HT4) receptors. The purpose of this study was to compare the effects of mosapride and the existing 5-HT4 receptor agonists on GI motility in conscious dogs and on various 5-HT4 receptor-mediated responses in vitro. In conscious dogs with force transducers implanted, mosapride (0.3-3 mg/kg i.v.) stimulated the antral motility without affecting the colonic motility. However, cisapride, zacopride and BIMU 8 (0. 1-1 mg/kg i.v.) stimulated both antral and colonic motility. The enhanced GI motility induced by mosapride or cisapride was antagonized by pretreatment with GR113808 (1 mg/kg bolus i.v., thereafter 1 mg/kg/hr infusion), a selective 5-HT4 receptor antagonist. In the receptor binding studies, mosapride inhibited [3H]-GR113808 binding to 5-HT4 receptor sites of guinea pig striatum with an IC50 value of 113 nM. In addition, mosapride caused relaxation of the carbachol-precontracted rat esophagus, enhanced the electrically evoked contractions of guinea pig ileum and evoked the contractions of guinea pig distal colon with EC50 values of 208, 73, and 3029 nM, respectively; this indicates that mosapride has a low affinity for colon than for the rest of the GI tract. In contrast, cisapride, zacopride or BIMU 8 had similar potencies in all preparations examined. In conclusion, these studies indicate that mosapride selectively stimulates upper GI motility in vivo and in vitro. These results also suggest heterogeneity of 5-HT4 receptors in the GI tract.[3]

Absorption, Distribution and Excretion
Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%. This study used a sheep model to investigate the placental transport of the novel prokinetic drug cisapride. Blood samples were collected via chronically implanted arterial catheters to study the pharmacokinetics of cisapride in lambs, pregnant ewes, and fetuses. Pharmacokinetic parameters were similar in lambs and adult sheep: half-life of 1.39-1.83 hours; total plasma clearance of 1998-2160 mL/kg/h; and AUC of 92.6-100.1 ng·h/mL. Based on parameters obtained after intravenous bolus injection, plasma concentrations following continuous cisapride infusion could be accurately predicted. Following a single intravenous bolus injection in ewes, cisapride underwent maternal-fetal transport. Cisapride crossed the placenta within 5 minutes of administration and reached equilibrium with maternal plasma within 20-30 minutes. The mean concentration ratio of fetal to maternal plasma was 0.71. Measurable amounts of cisapride are also present in amniotic fluid. The protein binding rates of cisapride in maternal and fetal plasma are 89.0% and 88.4%, respectively; its free concentration is four times that in humans. Cisapride can cross the sheep placental barrier. While the sheep placenta is less permeable than the human placenta, the higher free concentration of cisapride promotes placental transport.

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Metabolism/Metabolites
Hepatic metabolism. Extensively metabolized by cytochrome P450 3A4 enzymes.
Copyright IPA: ASHP This article describes the in vitro metabolism of cisapride using canine, rabbit, and rat liver fractions, and the identification of metabolites by high-performance liquid chromatography and mass spectrometry. The main biotransformation pathways are: oxidative N-dealkylation at pyridine nitrogen and aromatic groups, and hydroxylation at fluorophenyl or benzamide groups.
Hepatic metabolism. Extensively metabolized by cytochrome P450 3A4 enzymes.
Half-life: 6-12 hours

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Biological half-life
6-12 hours

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Cisapride has been withdrawn from the US market by the FDA due to cardiotoxicity. Because of its low concentration in breast milk, it is safe for breastfeeding women to use if needed.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding Rate
97.5%

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Interactions
Cisapride has been reported to increase the absorption of alcohol or benzodiazepines.
Concomitant use with anticholinergic drugs or other drugs with anticholinergic activity may antagonize the gastrointestinal motility effects of cisapride.
Cisapride may accelerate the absorption of cimetidine and ranitidine.
Adverse reactions may occur when used concomitantly with itraconazole, ketoconazole, or intravenous miconazole. Cisapride is contraindicated; concomitant use may lead to increased plasma concentrations of cisapride by these antifungal drugs through inhibition of the cytochrome P450 metabolic pathway; this has resulted in ventricular arrhythmias, including torsades de pointes, in patients taking cisapride and ketoconazole.
For more complete data on drug interactions of cisapride (8 drugs in total), please visit the HSDB record page.

[1]. J Pharmacol Sci. 2007, 105:207-210.

[2]. Cancer Biol Ther . 2005 Mar;4(3):295-301.

Cisapride is an amide formed by the condensation of 4-amino-5-chloro-2-methoxybenzoic acid and cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidine-4-amine. It was once used to treat gastroesophageal reflux disease and non-ulcer dyspepsia (in monohydrate or tartrate form), but due to its tendency to cause arrhythmias, it was completely withdrawn from the market in many countries, including the UK, and its use was restricted in other regions. It has a dual role as a serotonergic agonist, anti-ulcer agent, and gastrointestinal drug. It belongs to the piperidine, benzamide, monochlorobenzene, substituted aniline, organofluorine, and aromatic ether compounds. In many countries (including Canada), cisapride has been withdrawn from the market or its indications have been restricted due to reports that it can cause long QT syndrome, thereby inducing arrhythmias. The US Food and Drug Administration (FDA) has issued warning letters to healthcare professionals and patients regarding this risk. Cisapride is a substituted piperidinylbenzamide prokinetic drug. Cisapride promotes the release of acetylcholine from the intestinal plexus, thereby increasing gastrointestinal motility. Furthermore, studies have found that cisapride has the effects of a serotonin agonist (stimulating 5-HT4 receptors) and a 5-HT3 receptor antagonist. (National Cancer Institute, USA)
In many countries (including Canada), cisapride has been withdrawn from the market or its indications have been restricted due to reports that it can cause long QT syndrome, thereby inducing arrhythmias. The U.S. Food and Drug Administration (FDA) has issued warning letters to healthcare professionals and patients regarding this risk.
Cisapride is a substituted benzamide drug used for its prokinetic properties. It is used to treat gastroesophageal reflux disease, functional dyspepsia, and other conditions related to gastrointestinal motility disorders. (Martindale Pharmacopeia, 31st Edition)
See also: Cisapride monohydrate (active ingredient). Drug Indications Cisapride is indicated for the treatment of nocturnal heartburn in adult patients with gastroesophageal reflux disease (GERD). Mechanism of Action Cisapride works by stimulating serotonin 4 (5-HT4) receptors, thereby increasing the release of acetylcholine in the enteric nervous system, particularly the myenteric plexus. This leads to increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and duodenal bulb, and enhanced duodenal and jejunal peristalsis, thus accelerating gastric emptying and intestinal transit. Cisapride also works by increasing the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus. The release of acetylcholine enhances esophageal activity and increases esophageal sphincter tone, thereby improving esophageal clearance and reducing gastroduodenal reflux due to increased gastric and duodenal contractility and improved antral-duodenal coordination. Duodenogastric reflux is also reduced. Cisapride improves transit in the small and large intestines.

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Therapeutic Uses
Anti-ulcer medication; Gastrointestinal medication; Serotonin agonist
Cisapride is indicated for the treatment of nocturnal (and daytime/not included on the US product label/) heartburn symptoms, and esophagitis caused by reflux and delayed gastric emptying. Treatment can last up to 8 weeks; however, tolerance to cisapride may develop during treatment. /Included on the US product label/
Cisapride is indicated for the treatment of gastroparesis, including idiopathic gastroparesis, diabetic gastroparesis, and intestinal pseudo-obstruction. Treatment can last up to 8 weeks; however, tolerance to cisapride may develop during treatment. /Not included on the US product label/
...For patients with long-term laxative abuse, the dosage of laxatives should be reduced.
For more complete data on the therapeutic uses of cisapride (7 types), please visit the HSDB record page.

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Drug Warnings
Cisapride is generally well tolerated. The most common adverse reactions are gastrointestinal and neurological reactions, which also most often lead to discontinuation of the drug (usually due to intolerable diarrhea and/or abdominal pain). The most common gastrointestinal adverse reactions (such as diarrhea) are extensions of the drug's pharmacological effects. Due to the different pharmacological properties of the drugs, cisapride causes fewer neurological adverse reactions than metoclopramide, while diarrhea occurs more frequently. In placebo-controlled clinical trials in the United States, the most common adverse reactions to cisapride in adult patients with motility disorders (including those with gastroesophageal reflux disease) receiving cisapride were headache, diarrhea, abdominal pain, nausea, constipation, and rhinitis. The incidence of diarrhea, abdominal pain, constipation, bloating, and rhinitis appears to be dose-related, with patients taking 20 mg of cisapride four times daily being more likely to experience these adverse reactions than those taking 10 mg four times daily. Many adverse reactions reported after taking cisapride occurred at similar frequencies to the placebo group, and a causal relationship with the drug is often not definitively established.
In controlled clinical trials, more than 1% of patients taking cisapride reported dehydration. Limited evidence suggests that cisapride does not adversely affect glycemic control in patients with delayed gastric emptying and insulin-dependent (type 1) diabetes.
In controlled clinical trials, approximately 4% of patients taking cisapride experienced viral infections, of which 0.2% required discontinuation of the drug. In controlled clinical trials, approximately 2% of patients treated with cisapride reported fever, of which 0.1% discontinued the drug due to fever.
For more complete data on drug warnings for cisapride (6 of 6), please visit the HSDB record page.

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Pharmacodynamics
Cisapride is a parasympathomimetic drug that acts as a 5-hydroxytryptamine 4 (5-HT4) receptor agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of the neurotransmitter acetylcholine in the enteric nervous system. Cisapride stimulates upper gastrointestinal motility but does not stimulate gastric, bile, or pancreatic juice secretion. Cisapride enhances the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and duodenal bulb, and enhances duodenal and jejunal peristalsis, thereby accelerating gastric emptying and intestinal transit. It also increases the resting tone of the lower esophageal sphincter. Cisapride has almost no effect on colonic or gallbladder motility. Cisapride does not induce muscarinic or nicotinic receptor agonism, nor does it inhibit acetylcholinesterase activity.

C23H29CLFN3O4

465.95

465.183

C, 59.29; H, 6.27; Cl, 7.61; F, 4.08; N, 9.02; O, 13.73

81098-60-4

Cisapride monohydrate; 260779-88-2; 81098-60-4; 189888-25-3 (tartrate)

6917698

White to off-white solid powder

1.3±0.1 g/cm3

605.4±55.0 °C at 760 mmHg

107 - 111ºC

319.9±31.5 °C

0.0±1.7 mmHg at 25°C

1.593

3.12

2

7

9

32

581

2

C(C1C=C(Cl)C(N)=CC=1OC)(=O)N[C@@H]1CCN(CCCOC2C=CC(F)=CC=2)C[C@@H]1OC

DCSUBABJRXZOMT-IRLDBZIGSA-N

InChI=1S/C23H29ClFN3O4/c1-30-21-13-19(26)18(24)12-17(21)23(29)27-20-8-10-28(14-22(20)31-2)9-3-11-32-16-6-4-15(25)5-7-16/h4-7,12-13,20,22H,3,8-11,14,26H2,1-2H3,(H,27,29)/t20-,22+/m1/s1

4-amino-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide

R51619; R 51619; R-51619; Cisaprida; Cisapridum; (+-)-Cisapride; CHEBI:3720; Kaudalit; Prepulsid; Kinestase; Pridesia; Presid; Propulsid

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)

DMSO: 93~100 mg/mL (199.6~214.6 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)