piperidines and mosapride

The ideal medication for treatment of acid related diseases should have a rapid onset of action to promote hemostasis and resolution of symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion after a single oral administrations of lafutidine, is a newly synthesized H2-receptor antagonist, with mosapride 5 mg or lafutidine alone.. Ten Helicobacter pylori negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after a single oral administration of lafutidine 10 mg or lafutidine 10 mg with mosapride 5 mg (the lafutidine being administrated one hour after the mosapride). Each administration was separated by a 7-day washout period.. The average pH during the 4-hour period after administration of lafutidine 10 mg with mosapride 5 mg was higher than after lafutidine 10 mg alone (median: 5.25 versus 4.58, respectively; p = 0.0318). During the 3-4 hour study period, lafutidine 10 mg with mosapride 5 mg provided a higher pH, compared to lafutidine 10 mg alone (median: 7.28 versus 6.42; p = 0.0208).. In H. pylori negative healthy male subjects, an oral dose of lafutidine 10 mg with mosapride 5 mg more rapidly increased intragastric pH than lafutidine 10 mg alone.

Topics: Acetamides; Administration, Oral; Adult; Anti-Ulcer Agents; Benzamides; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Morpholines; Piperidines; Pyridines; Stomach; Time Factors

Pharmacologic stimulation of serotonin 5-HT4 receptors increased plasma active glucagon-like-peptide-1 (GLP-1) levels independent of feeding, and that pharmacologic stimulation of 5-HT4 receptors and pharmacologic inhibition of dipeptidyl peptidase-4 exerted synergic effects on plasma active GLP-1 levels and glucose tolerance in mice.

Topics: Animals; Benzamides; Blood Glucose; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Synergism; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Morpholines; Piperidines; Serotonin 5-HT4 Receptor Agonists; Uracil

It is known that 5-HT(4) receptors in the colon of guinea pigs show a distribution similar to that in humans. Thus, we examined the effects of mosapride citrate (mosapride) and cisapride, two 5-HT(4)-receptor agonists, on colonic motility in conscious guinea pigs implanted with force transducers. Mosapride and cisapride administered intragastrically at doses of 3 - 30 mg/kg significantly enhanced the colonic motility. The enhancing effect of mosapride was antagonized by atropine or GR113808, a 5-HT(4)-receptor antagonist, but not by methysergide, a 5-HT(1)- and 5-HT(2)-receptor antagonist; ondansetron, a 5-HT(3)-receptor antagonist; or CP-99994, a tachykinin NK(1)-receptor antagonist. In vitro receptor autoradiography showed that mosapride and cisapride inhibit the specific binding of [(125)I]-SB207710, a selective radioligand of 5-HT(4) receptors, in the colon of guinea pigs. These results suggest that mosapride enhances colonic motility through the 5-HT(4)-receptor activation in guinea pigs and may be useful for treating constipation in patients with colonic motility dysfunction.

Topics: Animals; Autoradiography; Benzamides; Colon; Dioxanes; Dose-Response Relationship, Drug; Gastrointestinal Motility; Guinea Pigs; Male; Morpholines; Piperidines; Radioligand Assay; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Ability of mosapride, a gastrokinetic agent, to bind to 5-HT4 receptor was examined in the stomach of human and guinea pig by in vitro receptor autoradiography. [125I]SB207710 binding sites were detected in the muscle layer including the myenteric plexus of the stomach from both humans and guinea pigs, although the binding was observed more clearly and densely in the stomach of guinea pigs than humans. Mosapride as well as SB204070 inhibited the binding of [125I]SB207710. Thus, mosapride possesses the ability to bind to 5-HT4 receptors of human stomach and may modulate the motility, as in the case of guinea pig stomach.

Topics: Aged; Animals; Benzamides; Binding Sites; Binding, Competitive; Dioxanes; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Gastrointestinal Agents; Guinea Pigs; Humans; Iodine Radioisotopes; Male; Middle Aged; Morpholines; Piperidines; Radioligand Assay; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin Antagonists; Stomach

The title compounds (6-9) were prepared and evaluated for serotonin 5-HT4 agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b]furan skeleton and 2,3-dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2-methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dimethylbenzo[b]furan-7-carboxamide (8d) hemifumarate were more potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D1, D2, serotonin 5-HT1, 5-HT2 and muscarine M1, M2 receptor binding activity in the in in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.

Topics: Animals; Benzamides; Benzofurans; Brain; Cisapride; Indoles; Morpholines; Piperidines; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Structure-Activity Relationship

The purpose of this study was to examine the effects of 5-HT4-receptor agonists cisapride, mosapride citrate (mosapride), and zacopride on action potentials (APs) in guinea pig isolated papillary muscles. Cisapride (0.1-3 microM) concentration-relatedly prolonged the duration of APs (APD) without affecting the other AP parameters. Mosapride and its main metabolite M1 (des-4-fluoro-benzyl-mosapride) did not affect APs at 10 microM. Zacopride at 10 microM shortened APD, and the APD-shortening effect was not affect by GR113808 (10 microM), a 5-HT4-receptor antagonist. The cisapride (1 microM)-induced prolongation of APD was not affected by GR113808 (10 microM), ritanserin (10 microM), a 5-HT2A/2C-receptor antagonist, or prazosin (10 microM), an alpha 1-receptor antagonist. The same concentrations of GR113808, ritanserin, and prazosin did not affect APD. Clofilium, a class III antiarrhythmic agent, prolonged APD; the effect was more pronounced at a stimulus frequency of 0.3 Hz than at 2.0 Hz. Cisapride did not exert such reverse use dependence, suggesting that its mechanism of action is different from that of clofilium. These results suggest that cisapride prolongs APD without involvement of 5-HT2, 5-HT4, or alpha 1 receptors. Mosapride is unlikely to induce the prolongation of electrocardiographic QT intervals correlated with the prolongation of APD in isolated ventricular muscles.

Topics: Action Potentials; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Anti-Arrhythmia Agents; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Electric Stimulation; Electrocardiography; Guinea Pigs; Heart; In Vitro Techniques; Male; Microelectrodes; Morpholines; Muscle, Smooth, Vascular; Papillary Muscles; Piperidines; Prazosin; Quaternary Ammonium Compounds; Serotonin Antagonists; Serotonin Receptor Agonists; Sympathetic Nervous System

In the present study the electrophysiological characteristics and the proarrhythmic potential of cisapride and a structurally related drug, mosapride, were compared. In the anesthetized guinea pig, cisapride and d-sotalol (0.01-10 micromol/kg i.v., n = 6) dose-dependently prolonged the duration of the monophasic action potential recorded from the left ventricle. The maximal lengthening was 18 +/- 3.2% at 1.0 micromol/kg (mean +/- S.E.M., P < .01 vs. base line) and 19 +/- 2.5% at 10 micromol/kg (P < .001) for cisapride and d-sotalol, respectively. In contrast, mosapride did not increase this variable. In a rabbit model of the acquired long QT syndrome, infusion of cisapride (0.3 micromol/kg/min for 10 min maximum, n = 6), but not mosapride or vehicle, was associated with a significant lengthening of the QTU interval (43 +/- 3.8 ms, P < .01). Furthermore, torsades de pointes appeared in two of the six rabbits given cisapride. In isolated rabbit Purkinje fibers (PF), cisapride increased the action potential duration (48 +/- 5.6% at 0.1 micromol/l, P < .01 vs. control, n = 4). Mosapride did not significantly influence the action potential duration (3 +/- 2.0% increase at 1.0 micromol/l, n = 6). However, after mosapride was washed out, the addition of cisapride (0.1 micromol/l) caused a 46 +/- 3.2% lengthening of the action potential duration (P < .01 vs. 1.0 micromol/l mosapride). Early afterdepolarizations and triggered activity appeared in four of eight cisapride-superfused PF stimulated at a very low frequency (0.1 Hz). In isolated rabbit cardiomyocytes, cisapride concentration-dependently blocked (IC50 = 9 nmol/l) the rapid component of the delayed rectifying K+ current (I(Kr)). Mosapride was approximately 1000-fold less potent in blocking I(Kr) (IC50 = 4 micromol/l). It is concluded that the electrophysiological characteristics of cisapride may explain the recently reported propensity to prolong the QT interval and to induce torsades de pointes in susceptible patients, although a structurally related benzamide, mosapride, did not appear to have electrophysiological features of relevance for induction of torsades de pointes in common with cisapride.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Benzamides; Cisapride; Guinea Pigs; Heart; In Vitro Techniques; Long QT Syndrome; Male; Morpholines; Piperidines; Purkinje Fibers; Rabbits; Structure-Activity Relationship

The influence of diabetic hyperglycemia on solid gastric emptying in rats was examined. Diabetes was produced by streptozotocin (STZ, 40 mg/kg i.v.), and diabetic hyperglycemia was observed from 1 day after the STZ injection. The gastric emptying of glass beads in the diabetic rats was significantly delayed compared with that in age-matched control rats at 1, 3 and 7 days after diabetes induction. A slight decrease in gastric emptying was observed in the diabetic rats from 2 to 52 weeks after the diabetes induction. We also investigated the influence of gastroprokinetic agents on STZ-induced diabetic gastroparesis and subdiaphragmatic vagotomy-induced gastroparesis in rats. The selective 5-HT3 receptor antagonists ramosetron (YM060), YM114 (KAE-393), granisetron and ondansetron, and the substituted benzamides (5-HT4 receptor agonist/5-HT3 receptor antagonists) cisapride mosapride and SC-53116 dose-dependently enhanced gastric emptying in normal rats. These compounds also reversed the impairment of diabetic gastroparesis rats at 7 days after the STZ injection, but higher doses were required. The solid gastric emptying in subdiaphragmatic vagotomized rats was also delayed. Ramosetron and the substituted benzamides cisapride and zacopride partially reversed the gastroparesis in the vagotomized rats. These results suggest that acute hyperglycemia is important mechanism for the delay of solid gastric emptying in diabetic rats. It is also suggested that selective 5-HT3 receptor antagonists and substituted benzamides enhance gastric emptying not only in normal rats but also in diabetic and vagotomized rats.

Topics: Animals; Benzamides; Benzimidazoles; Blood Glucose; Cisapride; Diabetes Mellitus, Experimental; Gastric Emptying; Gastrointestinal Motility; Gastroparesis; Granisetron; Male; Morpholines; Ondansetron; Piperidines; Pyrroles; Rats; Rats, Wistar; Serotonin Antagonists; Serotonin Receptor Agonists; Vagotomy

The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.

Topics: Animals; Benzamides; Chemical Phenomena; Chemistry; Cisapride; Dogs; Gastric Emptying; Gastrointestinal Agents; Male; Metoclopramide; Mice; Morpholines; Piperidines; Rats; Serotonin Antagonists; Structure-Activity Relationship

The effects of AS-4370 [4-amino-5-chloro-2-ethoxy-N-(4-(4-fluorobenzyl)-2 morpholinyl)methyl)benzamide citrate] on gastrointestinal (GI) motor activity were compared with those of cisapride and metoclopramide in conscious dogs with force transducers implanted chronically. In postprandial state, AS-4370 given 0.2 to 1 mg/kg i.v. or 1 mg/kg intraduodenally (i.d.) stimulated the antral and duodenal motor activity without affecting the colonic motor activity. Cisapride at 0.2 to 1 mg/kg i.v. or 1 mg/kg i.d. stimulated the motor activity in all sites of the GI tract from the stomach to the colon simultaneously. Metoclopramide, like AS-4370, stimulated the antral and duodenal motor activity, but its effect was less potent than that of AS-4370. AS-4370 did not stimulate the GI motor activity under treatment with atropine but stimulated it under vagotomy. Furthermore, AS-4370 did not potentiate the methacholine-induced antral contraction, whereas neostigmine at 10 micrograms/kg i.v. significantly enhanced it. AS-4370 at 1 mg/kg i.v. did not antagonize the inhibition of antral motor activity induced by i.v. infusion of dopamine (1 mg/kg/hr), whereas cisapride (0.5 mg/kg i.v.) and metoclopramide (1 mg/kg i.v.) antagonized it. In addition, the enhancement of GI motor activity induced by AS-4370 was not prevented by propranolol, prazosin, yohimbine, methysergide, ketanserin, ICS 205-930 or naloxone. 5- Hydroxytryptamine (5-HT) receptor desensitization induced by 5-HT (300 micrograms/kg/hr) in the antrum reduced the enhancement induced by AS-4370.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Cisapride; Dogs; Duodenum; Female; Gastrointestinal Agents; Gastrointestinal Motility; Jejunum; Male; Metoclopramide; Morpholines; Piperidines; Pyloric Antrum; Serotonin Antagonists