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%.
The placental transfer of cisapride, a new prokinetic agent, was studied in a sheep model. The pharmacokinetics of cisapride were studied in the lamb, the pregnant ewe, and the fetus by obtaining blood samples from chronically implanted arterial catheters. Comparable pharmacokinetic parameters were found in the lamb and the adult sheep: half-life, 1.39-1.83 hr; total plasma clearance, 1998-2160 ml/kg/hr; AUC, 92.6-100.1 ng.hr/ml. Cisapride plasma concentrations after continuous infusion were predicted correctly based on the parameters obtained after IV bolus. There was a materno-fetal transfer of cisapride following a single IV bolus administered to the mother. Cisapride crossed the placenta within 5 min and equilibrated with maternal plasma within 20 to 30 min after dosing. The average fetal-to-maternal plasma concentration ratio was 0.71. The amniotic fluid also contained measurable amounts of cisapride. The protein binding of cisapride in maternal and fetal plasma is 89.0% and 88.4%, respectively; the free fraction is 4 times larger than in humans. Cisapride crosses the ovine placental barrier. The sheep placenta is less permeable than the human placenta, but the higher free fraction of cisapride facilitates placental transfer.

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Metabolism / Metabolites
Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme.
IPA COPYRIGHT: ASHP The metabolism of cisapride in vitro using Liver fractions of dogs, rabbits, and rats and the metabolites identified by high performance LC and by MS are described. Main bi otransformat i on routes were oxi dat i ve N-dealkylat i on at the pi peri di ne ni trogen and aron at i c hydroxylat i on at the fluorophenyl or at the benzami de moi ety. ENG ~21 nq~_~n_~.
Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme.
Half Life: 6-12 hours

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Biological Half-Life
6-12 hours

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Cisapride was removed from the market in the United States by the U.S. Food and Drug Administration because of cardiac toxicity. Because of the low levels of cisapride in breastmilk, its use is acceptable in nursing mothers if it is required.
◉ 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.

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Protein Binding
97.5%

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Interactions
Cispride has been reported to increase the rate of absorption of /alcohol or benzodiazepines/.
Concurrent use /with anticholinergics or other medications with anticholinergic activity/ may antagonize the effects of cisapride on gastrointestinal motility.
Cisapride accelerates the absorption of cimetidine and rantidine.
Concurrent use of itraconazole, ketoconazole, or intravenous miconazole with cisapride is contraindicated; concurrent use may result in elevated plasma concentrations of cisapride through inhibition of the cytochrome p450 metabolic pathways by these antifungals; this has led to ventricular arrhythmias, including torsades des pointes, in patients taking cisapride and ketoconazole.
For more Interactions (Complete) data for CISAPRIDE (8 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 the amide resulting from formal condensation of 4-amino-5-chloro-2-methoxybenzoic acid with cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-amine. It has been used (as its monohydrate or as its tartrate) for the treatment of gastro-oesophageal reflux disease and for non-ulcer dyspepsia, but its propensity to cause cardiac arrhythmias resulted in its complete withdrawal from many countries, including the U.K., and restrictions on its use elsewhere. It has a role as a serotonergic agonist, an anti-ulcer drug and a gastrointestinal drug. It is a member of piperidines, a member of benzamides, a member of monochlorobenzenes, a substituted aniline, an organofluorine compound and an aromatic ether.
In many countries (including Canada) cisapride has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to cisapride, which predisposes to arrhythmias. The FDA issued a warning letter regarding this risk to health care professionals and patients.
Cisapride is a substituted piperidinyl benzamide prokinetic agent. Cisapride facilitates release of acetylcholine from the myenteric plexus, resulting in increased gastrointestinal motility. In addition, cisapride has been found to act as a serotonin agonist, stimulating type 4 receptors, and a serotonin 5-HT3 receptor antagonist. (NCI)
In many countries (including Canada) cisapride has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to cisapride, which predisposes to arrhythmias. The FDA issued a warning letter regarding this risk to health care professionals and patients.
A substituted benzamide used for its prokinetic properties. It is used in the management of gastroesophageal reflux disease, functional dyspepsia, and other disorders associated with impaired gastrointestinal motility. (Martindale The Extra Pharmacopoeia, 31st ed)
See also: Cisapride Monohydrate (active moiety of).

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Drug Indication
For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease.

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Mechanism of Action
Cisapride acts through the stimulation of the serotonin 5-HT₄ receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit.
Cisapride exerts its effect by increasing the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus. This release of acetylcholine increases esophageal activity and increases esophageal sphincter tone, thereby improving esophageal clearance and decreasing reflux of gastric and duodenal emptying as a result of increased gastric and duodenal contractility and antroduodenal coordination. Duodenogastric reflux is also decreased. Cisapride improves transit in both small and large bowel.

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Therapeutic Uses
Anti-Ulcer Agents; Gastrointestinal Agents; Serotonin Agonists
Cisapride is indicated for the symptomatic treatment of nocturnal (and daytime /Not included in US product labeling/) heartburn, and of esophagitis due to reflux and delayed gastric emptying. Treatment may continue for up to 8 weeks; however, tolerance to cisapride may develop at some point in therapy. /Included in US product labeling/
Cisapride is indicated in the treatment of gastroparesis, including idiopathic, diabetic, and intestinal pseudo-obstruction. Treatment may continue for up to 8 weeks; however, tolerance to cisapride may develop at some point in therapy. /NOT included in US product labeling/
... Reduce the consumption of laxatives in patients who chronically abuse these agents.
For more Therapeutic Uses (Complete) data for CISAPRIDE (7 total), please visit the HSDB record page.

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Drug Warnings
Cisapride generally is well tolerated. Adverse effects on the GI tract and nervous system are most common and those most frequently requiring discontinuance of the drug(usually because of intolerable diarrhea and/or abdominal pain). The most common adverse GI effects (e.g., diarrhea) are extensions of the drug's pharmacologic activity. Because of differences in the pharmacologic profiles of the drugs, adverse nervous system effects are less common with cisapride than with metoclopramide whereas diarrhea is more common with cisapride.
In adults receiving cisapride for motility disorder in US placebo-controlled clinical trials, including those with gastroesophageal reflux disease, the most frequent adverse effects of cisapride were headache, diarrhea, abdominal pain, nausea, constipation, and rhinitis. The frequency of diarrhea, abdominal pain, constipation, flatulence, and rhinitis appears to be dose dependent, occurring more frequently in patients receiving oral cisapride 20 mg 4 times daily than in those receiving 10 mg 4 times daily. Many adverse effects reported with cisapride occurred at a frequency similar to that associated with placebo, and a causal relationship to the drug often could not be established.
Dehydration was reported in more than 1% of patients receiving cisapride in controlled clinical trials. Limited evidence indicates that cisapride does not adversely affect glycemic control in insulin-dependent (type I) diabetic patients with delayed gastric emptying.
Viral infection occurred in about 4% of patients receiving cisapride in controlled clinical trails and required discontinuance of the drug in 0.2% of patients. Fever was reported in about 2% of patients receiving cisapride in controlled clinical trials and required discontinuance in 0.1%.
For more Drug Warnings (Complete) data for CISAPRIDE (6 total), please visit the HSDB record page.

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Pharmacodynamics
Cisapride is a parasympathomimetic which acts as a serotonin 5-HT₄ agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Cisapride does not induce muscarinic or nicotinic receptor stimulation, 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.)