piperidines and prucalopride

Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder.. This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non-pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this debilitating yet common condition.

Topics: Anesthesia, Epidural; Animals; Benzofurans; Chewing Gum; Cholinergic Agents; Contrast Media; Cyclooxygenase Inhibitors; Diatrizoate Meglumine; Digestive System Surgical Procedures; Enhanced Recovery After Surgery; Enteral Nutrition; Enteric Nervous System; Fluid Therapy; Gastrointestinal Agents; Gastrointestinal Motility; Ghrelin; Humans; Ileus; Inflammation; Intestinal Pseudo-Obstruction; Intubation, Gastrointestinal; Laparoscopy; Mast Cells; Piperidines; Postoperative Complications; Serotonin 5-HT4 Receptor Agonists; Sympathetic Nervous System; Sympatholytics

There has been no definitive synthesis of the evidence for any benefit of available pharmacological therapies in opioid-induced constipation (OIC). We conducted a systematic review and meta-analysis to address this deficit.. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials through to December 2012 to identify placebo-controlled trials of μ-opioid receptor antagonists, prucalopride, lubiprostone, and linaclotide in the treatment of adults with OIC. No minimum duration of therapy was required. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Effect of pharmacological therapies was reported as relative risk (RR) of failure to respond to therapy, with 95% confidence intervals (CIs).. Fourteen eligible randomized controlled trials (RCTs) of μ-opioid receptor antagonists, containing 4,101 patients, were identified. These were superior to placebo for the treatment of OIC (RR of failure to respond to therapy=0.69; 95% CI 0.63-0.75). Methylnaltrexone (six RCTs, 1,610 patients, RR=0.66; 95% CI 0.54-0.84), naloxone (four trials, 798 patients, RR=0.64; 95% CI 0.56-0.72), and alvimopan (four RCTs, 1,693 patients, RR=0.71; 95% CI 0.65-0.78) were all superior to placebo. Total numbers of adverse events, diarrhea, and abdominal pain were significantly commoner when data from all RCTs were pooled. Reversal of analgesia did not occur more frequently with active therapy. Only one trial of prucalopride was identified, with a nonsignificant trend toward higher responder rates with active therapy. Two RCTs of lubiprostone were found, with significantly higher responder rates with lubiprostone in both, but reporting of data precluded meta-analysis.. μ-Opioid receptor antagonists are safe and effective for the treatment of OIC. More data are required before the role of prucalopride or lubiprostone in the treatment of OIC are clear.

Topics: Alprostadil; Analgesics, Opioid; Benzofurans; Constipation; Female; Gastrointestinal Agents; Humans; Lubiprostone; Male; Naloxone; Naltrexone; Narcotic Antagonists; Peptides; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.

Topics: Antibodies, Monoclonal; Benzofurans; Carbamates; Drug Approval; Humans; Phenylalanine; Piperidines; Purines; Tetracyclines; United States; United States Food and Drug Administration

The objective of the current investigation was to develop a simple, rapid method for determining in-vivo 5-hydroxytryptamine type 4 receptor (5-HT4 R) occupancy in rat brain using non-radiolabelled SB207145 as a tracer for accelerating the drug discovery process.. In-vivo tracer optimization studies for tracer dose, survival intervals and brain distribution profile were carried out in rats. The tracer was pharmacologically validated using potent well-characterized 5-HT4 R ligands. The brain regional concentrations of tracer (SB207145); plasma and brain concentrations of 5-HT4 R ligands were quantified using high-performance liquid chromatography coupled with a tandem mass spectrometric detector (LC-MS/MS).. SB207145 showed a higher specific binding in striatum (1.96 ng/g) and lower binding in cerebellum (0.66 ng/g), which is consistent with findings of other published 5-HT4 R expression studies. Pretreatment with potent 5-HT4 ligands dose-dependently reduced striatal SB207145 concentration and the effective dose to achieve 50% receptor occupancy (ED50 ) values were 4.8, 2.0, 7.4, 9.9, 3.8 and 0.02 mg/kg for GR113808, piboserod, prucalopride, RS67333, TD8954 and PF04995274, respectively.. Results from the mass spectrometry approach to determine 5-HT4 R occupancy in rat brain are comparable with those reported using radiolabelled scintillation spectroscopy methods. In conclusion, the LC-MS/MS characterization permits use of tracer at a preclinical stage in high-throughput fashion as well as characterization of target expression.

Topics: Aniline Compounds; Animals; Benzofurans; Binding, Competitive; Brain; Drug Discovery; Indoles; Ligands; Male; Oxazines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Sulfonamides; Tandem Mass Spectrometry; Tissue Distribution

Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon.. Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'.. Prucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration).. Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Cholinesterase Inhibitors; Colon; Donepezil; Drug Synergism; Female; Gastrointestinal Motility; Humans; In Vitro Techniques; Indans; Male; Middle Aged; Muscle Contraction; Piperidines; Serotonin 5-HT4 Receptor Agonists

A UPLC-MS/MS assay was developed and validated for simultaneous quantification of acetylcholine (ACh), histamine (HA), tele-methylhistamine (t-mHA), and tele-methylimidazolacetic acid (t-MIAA) in rat cerebrospinal fluid (CSF). The biological stability of ACh in rat CSF was investigated. Following fit-for-purpose validation, the method was applied to monitor the drug-induced changes in ACh, HA, t-mHA, and t-MIAA in rat CSF following administration of donepezil or prucalopride. The quantitative method utilizes hydrophilic interaction chromatography (HILIC) Core-Shell HPLC column technology and a UPLC system to achieve separation with detection by positive ESI LC-MS/MS. This UPLC-MS/MS method does not require extraction or derivatization, utilizes a stable isotopically labeled internal standard (IS) for each analyte, and allows for rapid throughput with a 4 min run time. Without an acetylcholinesterase (AChE) inhibitor present, ACh was found to have 1.9±0.4 min in vitro half life in rat CSF. Stability studies and processing modification, including the use of AChE inhibitor eserine, extended this half life to more than 60 min. The UPLC-MS/MS method, including stabilization procedure, was validated over a linear concentration range of 0.025-5 ng/mL for ACh and 0.05-10 ng/mL for HA, t-mHA, and t-MIAA. The intra-run precision and accuracy for all analytes were 1.9-12.3% CV and -10.2 to 9.4% RE, respectively, while inter-run precision and accuracy were 4.0-16.0% CV and -5.3 to 13.4% RE, respectively. By using this developed and validated method, donepezil caused increases in ACh levels at 0.5, 1, 2, and 4h post dose as compared to the corresponding vehicle group, while prucalopride produced approximately 1.6- and 3.1-fold increases in the concentrations of ACh and t-mHA at 1h post dose, respectively, compared to the vehicle control. Overall, this methodology enables investigations into the use of CSF ACh and HA as biomarkers in the study of these neurotransmitter systems and related drug discovery efforts.

Topics: Acetylcholine; Animals; Benzofurans; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Drug Stability; Histamine; Hydrophobic and Hydrophilic Interactions; Imidazoles; Indans; Male; Methylhistamines; Piperidines; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

We have recently reported that serotonin(4) (5-HT(4)) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants.. We found that, in acute conditions, the 5-HT(4) agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4) agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT(1A) receptors, that was two to three times stronger when the 5-HT(4) agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound.. These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4) agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

Topics: Action Potentials; Aniline Compounds; Animals; Antidepressive Agents; Benzofurans; CA3 Region, Hippocampal; Citalopram; Cyclic AMP Response Element-Binding Protein; Drug Synergism; Fluvoxamine; Male; Motor Activity; Neurons; Phosphorylation; Piperazines; Piperidines; Pyridines; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT(4) receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pKi: 7.38-7.91) > or = Y-36912 (pKi: 7.03-7.85) = BIMU 1 (pKi: 6.92-7.78) > or = DAU 6236 (pKi: 6.79-7.99) > or = 5-HT (pKi: 5.82-7.29) > or = 5-MeOT (pKi: 5.64-6.83) > or = renzapride (pKi: 4.85-5.56). We obtained affinity values for the 5-HT4(b), (d) and (g) variants for RS67333 (pKi: 7:48-8.29), prucalopride (pKi: 6.86-7.37) and zacopride (pKi: 5.88-7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically.

Topics: Aniline Compounds; Animals; Benzamides; Benzimidazoles; Benzofurans; Binding Sites; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Chlorocebus aethiops; COS Cells; Cyclic AMP; Dose-Response Relationship, Drug; Humans; Indoles; Kinetics; Ligands; Piperidines; Protein Isoforms; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

It is known that 5-HT(4) receptor agonists increase sAPPalpha levels in the cortex and hippocampus of mice as well as in a model of Alzheimer's disease (AD). As sAPPalpha is thought to have pro-mnesic properties, we assessed whether its increase induces cognitive improvement in a spatial memory task and whether it reverses a scopolamine-induced memory deficit. Mice treated or not treated with scopolamine were trained in the Morris water maze for 3 days. Before the probe test, they received an injection of either a 5-HT(4) receptor agonist (prucalopride or RS 67333), or an acetylcholinesterase inhibitor (donepezil), or both drugs. As expected, scopolamine decreased performance, an effect that was not reversed by the drugs tested when injected alone. However, prucalopride (5 mg kg(-1), s.c.) acted synergistically with donepezil (0.75 mg kg(-1), s.c.) to counteract completely scopolamine-induced amnesia. Western blot analysis of tissue homogenates in the cortex and hippocampus shows that sAPPalpha levels did not differ between saline- and scopolamine-treated mice. Furthermore, a region-dependent drug action was observed since the scopolamine-treated mice display a tendency to increase sAPPalpha levels in the hippocampus after donepezil or in the cortex after prucalopride. Our results suggest that a combined treatment with a 5-HT(4) receptor agonist with an acetylcholinesterase inhibitor has beneficial effects on memory in mice. Moreover, it seems to enhance sAPPalpha levels in two brain regions highly affected in AD. Thus, a drug polytherapy could be interesting not only to enhance cognitive performance and decrease drawbacks but also to get the best action in each brain region.

Topics: Amyloid beta-Protein Precursor; Analysis of Variance; Aniline Compounds; Animals; Benzofurans; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Drug Synergism; Hippocampus; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Motor Activity; Nootropic Agents; Piperidines; Scopolamine; Serotonin 5-HT4 Receptor Agonists; Statistics, Nonparametric

A strategy to treat Alzheimer's disease (AD) is to increase the soluble form of amyloid precursor protein (sAPPalpha), a promnesic protein, in the brain. Because strong evidence supports beneficial effects of 5-hydroxytryptamine 5-HT(4) receptor agonists in memory and learning, we investigated the role of 5-HT(4) receptors on APP processing in 8 weeks-old male C57BL/6j mice.. Mice were given, subcutaneously, prucalopride or ML 10302 (s.c.), two highly selective 5-HT(4) receptor agonists and, up to 240 min later, the hippocampus and cortex were analysed by Western blot for sAPPalpha determination.. Prucalopride (5 or 10 mg kg(-1)) significantly increased sAPPalpha levels in the hippocampus and cortex, but did not modify the expression level of APP mRNA as detected by quantitative RT-PCR. A selective 5-HT(4) receptor antagonist, GR125487 (1 mg kg(-1), s.c.) inhibited prucalopride induced- increase in sAPPalpha levels. In addition, levels of sAPPalpha were increased by ML10302 only at 20 mg kg(-1) and was limited to the cortex. Also, prucalopride increased sAPPalpha levels in the cortex of a transgenic mouse model of AD, expressing the London mutation of APP. Furthermore, the combined injection of a selective acetylcholinesterase inhibitor, donepezil and prucalopride induced a synergic increase in sAPPalpha levels in the cortex and hippocampus.. Our results demonstrate that the 5-HT(4) receptor plays a key role in the non-amyloidogenic pathway of APP metabolism in vivo and give support to the beneficial use of 5-HT(4) agonists for AD treatment.

Topics: Aminobenzoates; Amyloid beta-Protein Precursor; Animals; Benzofurans; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Hippocampus; Indans; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; para-Aminobenzoates; Piperidines; RNA, Messenger; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

We recently identified a facilitory control exerted by serotonin4 (5-HT4) receptors on the in vivo firing activity of dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons. However, these findings were based on acute administrations of 5-HT4 receptor agonists and antagonists, which were active only in a subpopulation of 5-HT neurons. We had no evidence that this influence was significant when considering the entire DRN, nor if it was persistent after chronic treatments. In addition, the poor distribution of 5-HT4 receptors within the DRN raised the question of the neuroanatomical bases underlying this control.. Here we show that the subacute intraperitoneal (IP) injection of the 5-HT4 receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before the beginning of recordings augment the mean firing rate of DRN neurons by 40% and 66%, respectively. These increases remain stable when the compounds are administered continuously during 3 and 21 days; the effects of the 3-day treatment are blocked by the 5-HT4 receptor antagonist GR 125487 (1000 microg/kg, intravenous [i.v.]). In addition, stereotaxic microinjections of herpes simplex viruses, transformed to overexpress 5-HT4 receptors, increase DRN 5-HT neuronal mean activity when performed in the medial prefrontal cortex (mPFC) but not in the striatum or in the hippocampus.. This finding suggests the existence of a 5-HT(4)-dependent activation of DRN that may involve the mPFC, unveiling the 5-HT4 receptor as a putative player in the physiopathology of several disorders related to central 5-HT dysfunction.

Topics: Aniline Compounds; Animals; Benzofurans; Electrophysiology; Extracellular Space; Feedback; Frontal Lobe; Gene Transfer Techniques; Genetic Vectors; Herpesvirus 1, Human; In Situ Hybridization; Indoles; Iontophoresis; Male; Neurons; Piperidines; Pyramidal Cells; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; RNA Probes; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

1. This study investigates whether the cholinergic neurones, innervating the human proximal stomach, can be modulated by nitric oxide (NO) or vasoactive intestinal polypeptide (VIP), or via presynaptic muscarinic, alpha(2)- or 5-hydroxytryptamine(4) (5-HT(4)-) receptors. 2. Circular muscle strips, without mucosa, were incubated with [(3)H]-choline to incorporate [(3)H]-acetylcholine into the cholinergic transmitter stores. The basal and electrically-induced release of tritium and [(3)H]-acetylcholine were analysed in a medium containing guanethidine (4 x 10(-6) M), hemicholinium-3 (10(-5) M), physostigmine (10(-5) M) and atropine (10(-6) M). Tissues were stimulated twice for 2 min (S(1) and S(2): 40 V, 1 ms, 4 Hz) and drugs were added before S(2). 3. The NO synthase inhibitor L-N(G)-nitroarginine methyl ester (3 x 10(-4) M) and the NO donor sodium nitroprusside (10(-5) M), as well as VIP (10(-7) M) did not influence the basal release nor the electrically-evoked release. 4. The alpha(2)-adrenoceptor agonist UK-14,304 (10(-5) M) significantly inhibited the electrically-evoked release of [(3)H]-acetylcholine, and this was prevented by the alpha(2)-adrenoceptor antagonist rauwolscine (2 x 10(-6) M). 5. The 5-HT(4)-receptor agonist prucalopride (3 x 10(-7) M) significantly enhanced the electrically-evoked release of [(3)H]-acetylcholine, and the 5-HT(4)-receptor antagonist SB204070 (10(-9) M) prevented this. 6. When atropine (10(-6) M) was omitted from the medium and added before the second stimulation, it significantly increased the release of [(3)H]-acetylcholine. 7. These results suggest that the release of acetylcholine from the cholinergic neurones, innervating the circular muscle in the human proximal stomach, can be inhibited via presynaptic muscarinic auto-receptors and alpha(2)-adrenoceptors, and stimulated via presynaptic 5-HT(4)-receptors. No evidence for modulation by NO or VIP was obtained.

Topics: Acetylcholine; Adrenergic alpha-Agonists; Adult; Aged; Aged, 80 and over; Atropine; Benzofurans; Brimonidine Tartrate; Dioxanes; Enzyme Inhibitors; Evoked Potentials; Female; Gastric Fundus; Gastrointestinal Agents; Humans; Male; Middle Aged; Muscarinic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Piperidines; Quinoxalines; Receptors, Cholinergic; Receptors, Muscarinic; Receptors, Presynaptic; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Receptors, Vasoactive Intestinal Peptide; Serotonin Antagonists; Stomach; Synaptic Transmission; Vasoactive Intestinal Peptide; Yohimbine

Prucalopride is a novel enterokinetic compound and is the first representative of the benzofuran class. We set out to establish its pharmacological profile in various receptor binding and organ bath experiments. Receptor binding data have demonstrated prucalopride's high affinity to both investigated 5-HT(4) receptor isoforms, with mean pK(i) estimates of 8.60 and 8.10 for the human 5-HT(4a) and 5-HT(4b) receptor, respectively. From the 50 other binding assays investigated in this study only the human D(4) receptor (pK(i) 5.63), the mouse 5-HT(3) receptor (pK(i) 5.41) and the human sigma(1) (pK(i) 5.43) have shown measurable affinity, resulting in at least 290-fold selectivity for the 5-HT(4) receptor. Classical organ bath experiments were done using isolated tissues from the rat, guinea-pig and dog gastrointestinal tract, using various protocols. Prucalopride was a 5-HT(4) receptor agonist in the guinea-pig colon, as it induced contractions (pEC(50)=7.48+/-0.06; insensitive to a 5-HT(2A) or 5-HT(3) receptor antagonist, but inhibited by a 5-HT(4) receptor antagonist) as well as the facilitation of electrical stimulation-induced noncholinergic contractions (blocked by a 5-HT(4) receptor antagonist). Furthermore, it caused relaxation of a rat oesophagus preparation (pEC(50)=7.81+/-0.17), in a 5-HT(4) receptor antagonist sensitive manner. Prucalopride did not cause relevant inhibition of 5-HT(2A), 5-HT(2B), or 5-HT(3), motilin or cholecystokinin (CCK(1)) receptor-mediated contractions, nor nicotinic or muscarinic acetylcholine receptor-mediated contractions, up to 10 microM. It is concluded that prucalopride is a potent, selective and specific 5-HT(4) receptor agonist. As it is intended for treatment of intestinal motility disorders, it is important to note that prucalopride is devoid of anti-cholinergic, anticholinesterase or nonspecific inhibitory activity and does not antagonise 5-HT(2A), 5-HT(2B) and 5-HT(3) receptors or motilin or CCK(1) receptors.

Topics: Acetylcholine; Animals; Benzofurans; Binding, Competitive; Carbachol; Cell Line; CHO Cells; Colon; Cricetinae; Dioxanes; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Esophagus; Female; Gallbladder; Gastrointestinal Agents; Granisetron; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Indoles; Indomethacin; Male; Motilin; Muscle Contraction; Piperidines; Rabbits; Rats; Rats, Wistar; Receptors, Cholecystokinin; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sincalide; Stomach; Sulfonamides; Vasodilator Agents