• cisapride;
  • constipation;
  • 5-HT4 receptor;
  • prucalopride;
  • tegaserod


  1. Top of page
  2. Abstract
  3. Introduction
  4. The 5-HT4 receptor as a target for prokinetic drugs
  5. 5-HT4 receptor agonists
  6. Conclusion
  7. Acknowledgements
  8. References

Abstract  5-Hydroxytryptamine4 (5-HT4) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT4 receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT4 receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K+ channel and tegaserod: 5-HT1 and 5-HT2 receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT4 receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT4 receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT4 receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT4 receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT4 receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders.




calcitonin gene-related peptide


dopamine transporter




gastro-oesophageal reflux disease




human ether-a-go-go-related gene




irritable bowel syndrome


intrinsic primary afferent neurone


longitudinal muscle myenteric plexus preparation


non-adrenergic non-cholinergic


noradrenaline transporter


nitric oxide




receptor activated solely by synthetic ligands


serotonin transporter


vasoactive intestinal peptide


  1. Top of page
  2. Abstract
  3. Introduction
  4. The 5-HT4 receptor as a target for prokinetic drugs
  5. 5-HT4 receptor agonists
  6. Conclusion
  7. Acknowledgements
  8. References

Serotonin [5-hydroxytryptamine (5-HT)], a ubiquitous signalling molecule, exerts its actions by interacting with seven receptor subtypes.1 It is involved in a variety of functions in the brain and periphery. 5-HT is synthesized by serotonergic neurones in the central nervous system but the largest amount of 5-HT in the body is found in the gut, specifically in the enterochromaffin (EC) cells of the GI mucosa and to a smaller extent in descending interneurones. After a meal, EC cells secrete large amounts of 5-HT, the excess moving into the portal circulation and intestinal lumen.2 Virtually all 5-HT in the blood originates from mucosal EC cells. Platelets avidly take up 5-HT and store it in dense granules; platelets themselves are incapable of synthesizing 5-HT.3 Since its discovery almost 60 years ago, extensive research on 5-HT has generated a plethora of therapeutic agents (agonists, antagonists and re-uptake inhibitors), some of which have had a major impact on disease management.4

The role of 5-HT in the gut is complicated by its interactions with different receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7) present in the GI tract. All classes of the 5-HT receptor family, except for the ligand-gated 5-HT3 receptor, are members of the seven transmembrane-spanning G protein-coupled receptor family.1 Besides the 5-HT3 receptors, 5-HT4 receptors are the most thoroughly studied subtype with regard to gut function. Together with 5-HT6 and 5-HT7 receptors, 5-HT4 receptors are positively coupled to Gs proteins, resulting in stimulation of adenylyl cyclase and increase in cellular cyclic AMP (cAMP). Almost 20 years ago, the first description of the 5-HT4 receptor and its pharmacological characterization was made by Dumuis et al., who reported 5-HT4 receptor-mediated stimulation of adenylyl cyclase by 5-HT in cultured mouse embryonic colliculi neurones.5 After the initial discovery of 5-HT4 receptors, it was rapidly recognized that gastrokinetic benzamides such as metoclopramide, cisapride and renzapride were agonists at this receptor in mouse embryo colliculi neurones and guinea-pig hippocampus.6–8 It is now well-established that 5-HT4 receptors are widely expressed in the body.9 In the periphery, 5-HT4 receptor activation has been shown to be involved in many responses in different organs such as the GI tract, the heart and the urinary bladder [for review, see Ref. (9)]. In the brain, the highest expression of 5-HT4 receptors is found in limbic structures, hippocampus and basal ganglia, which are anatomical structures linked to cognition. Consequently, 5-HT4 receptors have been implicated in a variety of pathological disorders and constitute a valuable target for the design of new drugs.

Many C-terminal splice variants of the 5-HT4 receptor have been described that all are positively coupled to cAMP. In addition, several splice variant-specific signal transduction cascades have been described.10 To date it is not realistic to imagine the design of selective ligands for a given isoform as the variations in the receptor sequence are located intracellularly. However, the concept of agonist-directed trafficking of the stimulus response might open up new avenues in this direction.

The 5-HT4 receptor as a target for prokinetic drugs

  1. Top of page
  2. Abstract
  3. Introduction
  4. The 5-HT4 receptor as a target for prokinetic drugs
  5. 5-HT4 receptor agonists
  6. Conclusion
  7. Acknowledgements
  8. References

The effect of 5-HT4 receptor activation in the GI tract has been studied extensively and varies by the region as well as the species under study. The involvement of 5-HT4 receptors in peristalsis in humans, rat, mouse and guinea-pig is well established. Mucosal stimulation induces release of 5-HT from EC cells, activating intrinsic primary afferent neurones (IPANs), which then release acetylcholine (ACh) and calcitonin gene-related peptide (CGRP). These neurotransmitters connect via interneurones to ascending excitatory (releasing ACh and/or tachykinins) and descending inhibitory (releasing nitric oxide (NO) and/or vasoactive intestinal peptide (VIP) and/or ATP) motor neurones, resulting in ascending contraction and descending relaxation. Radioligand binding and functional studies in the intestine suggest that 5-HT4 receptors are present in all segments of the human GI tract and are expressed on EC cells, IPANs, interneurones and efferent neurones of the myenteric plexus and smooth muscle cells, and their activation can thereby affect all components of the peristaltic reflex.3,11,12

In different species, including pig and humans, inhibitory 5-HT4 receptors are expressed on EC cells, thereby mediating autoregulation of 5-HT release.13 Activation of 5-HT4 receptors on IPANs might either initiate or strengthen the peristaltic reflex.3,14–18 On their turn, presynaptically located 5-HT4 receptors on myenteric interneurones can increase reflex activity.19 5-HT4 receptors are also present on the efferent limbs of the peristaltic reflex. Activation of these 5-HT4 receptors on efferent myenteric cholinergic excitatory neurones, leading to enhanced ACh release and hence increased contraction, is probably the predominant mechanism by which 5-HT4 receptor agonists affect GI motility. This has been shown in the human, porcine, canine, rat, murine and guinea-pig stomach,20–26 in guinea-pig ileum,27 and in the human, canine and guinea-pig colon.19,28,29 In addition, 5-HT4 receptors are expressed on non-adrenergic non-cholinergic (NANC) excitatory neurones in the guinea-pig19,30 and rat23 stomach and guinea-pig ileum31 and on inhibitory neurones in the murine stomach32 and guinea-pig and human colon.33,34 5-HT4 receptors causing relaxation are present on smooth muscle in the rat oesophageal muscularis mucosae,35 stomach36 and ileum37 and in canine and human large intestine.38,39 Besides these effects on the motor pathways, 5-HT4 receptor activation affects reflex activity that regulates intestinal secretion, thereby increasing HCO3 secretion in the duodenum of mouse and rat and in Cl secretion in the human and porcine small intestine and human and rat colon.40–48

This promiscuous expression profile of 5-HT4 receptors might contribute to regional and/or time-coordinated relaxation–contraction mechanisms, which are essential for GI function. For instance, in the canine colon, 5-HT4 receptor-mediated relaxation of the circular muscle is almost absent in the ascending colon, but increases towards the rectum.39 In addition, 5-HT4 receptors on cholinergic neurones mediate contractility in the proximal to middle, but not the distal, region of the canine large intestinal longitudinal muscle layer.28 These regional differences might provide a basis for a coordinated action in the colon upon stimulation with a 5-HT4 receptor agonist.

It is clear from the above that drugs that act as 5-HT4 receptor agonists are potent prokinetic agents.3,12,49 They have considerable therapeutic potential to treat patients with GI motility disorders, such as constipation, constipation-predominant irritable bowel syndrome (c-IBS), gastroparesis and gastro-oesophageal reflux disease (GORD).50,51 These disorders are both common and debilitating, and there is a need for safe and effective treatments. To meet this need, many efforts have been directed towards the development of 5-HT4 receptor agonists (Table 1). With the exception of SL65.0155 and PRX-03140, all these agonists were selected on the basis of their potential to treat GI motility disorders, highlighting the importance of this receptor in GI research. The clinical development of the older generation of compounds, which have poor 5-HT4 receptor selectivity, has been complicated by the occurrence of rare side effects. Although these adverse events were not 5-HT4 receptor-related, they have influenced the perception on the use of 5-HT4 receptor agonists in GI disorders and created confusion as regards the risk–benefit profile of 5-HT4 receptor agonists. However, the newer generation of selective 5-HT4 receptor agonists is devoid of off-target effects. Furthermore, we show in this review that 5-HT4 receptor agonists should be considered on an individual basis, based on the many 5-HT4 receptor-related differences.

Table 1.   Receptors at which gastrokinetic and enterokinetic agents, acting primarily at 5-HT4 receptors, interact at therapeutic doses
CompoundCompanyPhaseMode of action
  1. Only compounds that entered clinical trials are included.

  2. +, agonist, −, antagonist.

  3. *See text for receptor subtypes.

  4. †Compound on the market.

  5. ‡Restricted availability.

  6. §M0003 = R149402; M0004 = R199715.

  7. ¶Mainly its main metabolite.

  8. **Preregistration.

Metoclopramide (PrimperanTM)Sanofi-AventisM†+  
CleboprideAlmirall ProdesfarmaM†+  
Cisapride (PrepulsidTM)Johnson & JohnsonM‡+  
Tegaserod (ZelnormTM)NovartisM‡+ + 
Prucalopride (ResolorTM)MovetisIII**+    
ATI-7505ARYx TherapeuticsII+    
AU-228 (-224)Abbott, Hokuriku SeiyakuI+    

5-HT4 receptor agonists

  1. Top of page
  2. Abstract
  3. Introduction
  4. The 5-HT4 receptor as a target for prokinetic drugs
  5. 5-HT4 receptor agonists
  6. Conclusion
  7. Acknowledgements
  8. References

An interesting characteristic of 5-HT4 receptors is their ability to be activated by a wide range of compounds from very different chemical classes.9 The first prokinetic benzamide, metoclopramide (Fig. 1), which was later found to be a ligand for both 5-HT3 and 5-HT4 receptors, played an important role in the discovery of potent and selective 5-HT4 receptor ligands available today and has been the progenitor of the benzamide class. It was characterized as a gastric prokinetic agent with dopamine (D2) receptor antagonistic properties (Table 1). Clebopride was designed by modifiying the amino chain of metoclopramide, resulting in a strengthening of the affinity for D2 dopamine receptors. Nevertheless, the introduction of other substitutions resulted in the discovery of potent gastrokinetic compounds devoid of antidopaminergic properties, with cisapride (Fig. 1) being the first representative of this family.9 New 5-HT4 receptor agonists were also designed departing from the structure of 5-HT, as 5-HT is a potent agonist at 5-HT4 receptors. An example is tegaserod (Fig. 1) which is an indole carbazimidamide derivative of 5-HT. Compared with 5-HT, tegaserod has a guanidine moiety rather than a protonated amine in the indole side chain.52 Prucalopride (Fig. 1) is the first representative of a new chemical class, the dihydrobenzofurancarboxamide compounds. Important differences between these 5-HT4 receptor agonists are highlighted in the following sections and we show that 5-HT4 receptor agonists should be considered on an individual basis, rather than generalizing agonist-specific observations.


Figure 1.  Chemical structure of 5-HT and the 5-HT4 receptor agonists metoclopramide, renzapride, cisapride, prucalopride and tegaserod.

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Differences unrelated to 5-HT4 receptors: selectivity

The selectivity of 5-HT4 receptor agonists has proven to be an important determinant of the benefit/risk profile and ultimately their clinical success. Non-selectivity at 5-HT4 receptors provides an explanation for most of the differences observed between the different 5-HT4 receptor agonists on the market (Fig. 2). Metoclopramide (PrimperanTM) was the first compound to be used in GI hypomotility disorders and has been used in clinical practice for many years. However, its lack of selectivity continues to limit its more widespread use. In the same period, cisapride (PrepulsidTM) was introduced for the treatment of symptoms of severe dyspepsia, gastroparesis, pseudo-obstruction, paediatric reflux and nocturnal heartburn. After its successful use for more than 10 years, rare reporting of cardiovascular side effects started to emerge, notably in patients with predisposing conditions like a history of cardiac disease or the simultaneous use with other medications that inhibit cisapride’s metabolism; it is now only available under specific conditions. Although these adverse events were not 5-HT4 receptor-related, they have influenced the perception on the use of 5-HT4 receptor agonists in GI disorders. This was further corroborated by a recent request of the Food and Drug Administration (FDA) to suspend marketing of another 5-HT4 receptor agonist, tegaserod (ZelnormTM), which was used for the management of c-IBS and constipation since 2004. Reviewing some of the clinical and postmarketing data, the FDA got concerned about the possible link between use of tegaserod and increased risk of ischaemic adverse events. Recently, the FDA has permitted restricted use of the drug. Metoclopramide, cisapride and tegaserod are not 5-HT4 receptor-selective and the interaction with multiple receptors may contribute to their effect profile.


Figure 2.  Selectivity of the 5-HT4 receptor receptor agonists cisapride, tegaserod and prucalopride. Binding affinities (pKi) were obtained from the literature and from screening experiments performed at J&J Pharmaceutical Research and Development. Results are shown for binding at human (h), mouse (m) or rat (r) receptors or transporters. Each circle represents a single experimental value; for filled circles, the receptor or transporter studied is indicated. pKi values for the 5-HT4 receptor that were obtained in competitive binding experiments with a radiolabelled antagonist are shown in red, while those obtained in experiments with a radiolabeled agonist are shown in green. Because the labeled antagonist does not differentiate between high and low affinity states of the receptor, affinity values obtained in these experiments slightly underestimates the agonist’s affinity. Therefore, the affinity of tegaserod for 5-HT4 receptors is expected to be a little higher than indicated. Discrepancies exist between affinity values of tegaserod at 5-HT2A, 5-HT2B and 5-HT2C receptors that are reported in the literature or obtained from J&J.

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Dopamine receptors  Metoclopramide has clear dopamine receptor antagonistic properties. This contributes to its favourable and widely accepted antiemetic function, as dopamine produces nausea and vomiting through stimulation of the medullary chemoreceptor trigger zone.53 Additionally, as dopamine slows gastric emptying, metoclopramide might relieve symptoms in patients suffering from upper GI motility disorders such as functional dyspepsia.54 On the other hand, the compound is not free of side effects. Metoclopramide induces prolactin release by its antagonism at dopamine receptors at the level of the pituitary gland.55 Additionally, certainly with high doses, blocking striatal dopamine receptors can result in extrapyramidal side effects56 which halted the widespread acceptance of the drug.

5-HT3 In addition to being a D2 receptor antagonist, metoclopramide is a 5-HT3 receptor antagonist.57 It shares this property with renzapride and mosapride and to a lesser extent with cisapride or its major metabolite. As chemotherapeutic agents are known to elicit abnormal 5-HT release in the gut, blocking 5-HT3 receptors on intestinal afferents can decrease emesis associated with chemotherapy. On the other hand, blocking 5-HT3 receptors also has clinical relevance as in chronic diarrhoea this blockade reduces intestinal contractility, slows colonic transit and increases fluid absorption.58 Indeed, the most common side effect observed with the 5-HT3 receptor antagonist alosetron is constipation. This may explain why for example cisapride and renzapride exert potent prokinetic effects in the upper GI tract but have less clear effects on colonic motility.12 There is, however, some concern about a possible association of 5-HT3 antagonism with ischaemic colitis, as observed with selective 5-HT3 receptor antagonists including alonsetron and cilansetron.59,60 A 5-HT4 receptor agonist that also antagonizes 5-HT3 receptors might thus be less applicable in constipation-associated disorders, but might provide an additional antinausea function.

hERG  The concern about the potential for ventricular arrhythmias when using 5-HT4 receptor agonists mainly originates from the ability of cisapride to block the cardiac human ether-a-go-go-related gene (hERG) potassium channel, with associated prolongation of the repolarization phase of the ventricular action potential and QT interval. The reported IC50 values for the blocking effect of cisapride on the hERG channel vary between 6.5 and 44.5 nmol L−1 61,62 with the exception of Potet et al.63 who reported an IC50 of 240 nmol L−1. For comparison, the affinities of renzapride, mosapride, tegaserod and prucalopride for the hERG channel all are in the micromolar range which makes this unfavourable interaction most pronounced for cisapride63 (Fig. 2). Cisapride displays little (<10-fold) selectivity for 5-HT4 receptors relative to its hERG channel affinity. This lack of selectivity likely underlies the rare cardiac side effects observed with cisapride. In patients with predisposing conditions (pre-existing cardiac disease, concomitant use of CYP3A4 inhibitors), cisapride therapy has been associated with cardiac disturbances, including QT prolongation, syncope and ventricular arrhythmia. In the class of 5-HT4 receptor agonists, this property is unique to cisapride.

5-HT1 Tegaserod, in addition to its affinity for 5-HT4 receptors, has affinity for 5-HT1A, 5-HT1B and 5-HT1D receptors (only 4- to 50-fold lower than for 5-HT4; Fig. 2),9,30,64 and thereby constitutes the only 5-HT4 receptor agonist with known high affinity for 5-HT1 receptors. Tegaserod is an agonist at 5-HT1B/D receptors [results of pilot (n = 4) in vitro studies with 5-HT1B-transfected HEK 293 cells: pEC50 = 6.2, maximal effect: 77% relative to the effect of the 5-HT1B/D agonist alniditan]. Its agonism at 5-HT1B/D receptors might be beneficial by affecting its prokinetic effects, because in humans this action has been shown to cause a relaxation of the gastric fundus, a delay of gastric emptying and a stimulation of interdigestive small intestinal motility.65 However, in the rat, 5-HT causes acute gastric mucosal injury probably due to the activation of 5-HT1D receptors.66 Activation of these receptors has also been shown to cause vasoconstriction.67 Recently tegaserod has been associated with a number of possible ischaemic cardiovascular adverse events, including rare cases of myocardial infarction, unstable angina and stroke, especially in patients with predisposing conditions.68 It is postulated that these effects may be related to vasoconstriction mediated by 5-HT1B receptors in the vascular wall. This is also observed with 5-HT and triptans, compounds with an indole nucleus similar to tegaserod.

5-HT2 Tegaserod is also a high-affinity 5-HT2A and 5-HT2B receptor antagonist69, a property it shares with cisapride, an antagonist at 5-HT2A receptors. In the human colon, 5-HT2B receptor activation by exogenous 5-HT increases colonic muscle contractions.69 In addition, animal studies have reported the contraction of gastric muscle through 5-HT2A and 5-HT2B receptors.3,70 Therefore, it is possible that the antagonistic properties at 5-HT2A/2B receptors influence their prokinetic activity. Antagonism at 5-HT2B receptors might also have contributed to the ischaemic cardiovascular events of tegaserod because endothelial 5-HT2B receptors mediate vasorelaxation.71,72 However, to the best of our knowledge, no ischaemic events have been reported with other clinically used compounds with 5-HT2B antagonistic properties.

Monoamine transporters  Tegaserod has recently been shown to inhibit the 5-HT, dopamine and noradrenaline transporters, serotonin transporter (SERT), dopamine transporter (DAT) and noradrenaline transporter (NAT), respectively, albeit with low potency.73 This is also reflected in the binding affinity of tegaserod at these transporters (Fig. 2). As tegaserod has a bioavailability of only 10% and approximately two-thirds of tegaserod is excreted unchanged in faeces, most of the drug is available to act locally on EC cells and local high concentrations of the drug might therefore be reached to inhibit SERT, which might add to the prokinetic action of tegaserod. An increase in the availability of 5-HT might, however, induce receptor desensitization, reducing the efficacy of tegaserod with chronic usage.

The emerging link between the benefit–risk profile of 5-HT4 receptor agonists and their selectivity resulted in the synthesis of selective agonists. Prucalopride, Prx-03140, ATI-7505, SL65.0155 and M0003 are the clinically most advanced compounds. The selectivity of these compounds for the 5-HT4 receptor differentiates them from other 5-HT4 receptor agonists. Prucalopride is the first selective high-affinity 5-HT4 receptor agonist. Affinity for other receptors was detected only at concentrations which exceed its Ki value for the 5-HT4 receptor with a factor of at least 200.30 The selectivity of prucalopride is also underscored by the observation in vivo that all its induced effects could be blocked by a 5-HT4 receptor antagonist.74 Therefore, prucalopride and other selective 5-HT4 receptor agonists may offer an attractive, effective and safe alternative for patients suffering from hypomotility disorders such as chronic constipation.

Differences related to 5-HT4 receptors

In vitro

Agonist–receptor interaction.  The structural features that define the 5-HT4 ligands are an aromatic moiety, a coplanar hydrogen acceptor group such as the carbonyl function, and a basic nitrogen atom. Despite these common features, it has been demonstrated that triptamines (5-HT, tegaserod) and benzamides (metoclopramide, renzapride, cisapride) have different pharmacophores.52,75 The mutation of the conserved Asp100 generates a 5-HT4 receptor activated solely by synthetic ligands (RASSL). The 5-HT4 RASSL is insensitive to 5-HT and tegaserod, which can be explained by the lack of binding of these compounds to the mutant receptor.76 The 5-HT4 receptor antagonist GR113808 is still able to bind to the mutant receptor, which can also be stimulated by numerous synthetic agonists from different chemical classes, including the benzamides metoclopramide, renzapride and cisapride. These compounds all have a bulky substitute of the basic nitrogen, most of them with the basic nitrogen included in a structured ring (Fig. 1), necessary to interact in a hydrophobic pocket of the receptor.77 In contrast, the highly conserved Asp100 is known to make an ionic bond with the protonated amine of 5-HT derivatives. Taken together, this suggests that tegaserod on the one hand and the benzamides and prucalopride on the other hand, use different binding pockets on the 5-HT4 receptor.

It is becoming increasingly recognized that seven-transmembrane receptors are allosteric proteins that can adopt numerous conformations which can activate different transduction pathways by agonist-directed stimulus trafficking (ligand-directed signalling).78,79 Therefore, a linear view of efficacy whereby a single receptor activation state (two-state model, where the receptor is either on or off) triggers all possible receptor interactions with a cell is no longer supported. The existence of different receptor conformations has been shown for constitutively active mutants of the 5-HT4 receptor80 and for the full, partial and inverse agonist-liganded 5-HT4 receptor.81,82 In addition, the efficacy of a partial 5-HT4 receptor agonist is likely due to the stabilization of an agonist-specific conformational state.82 The efficacy of a certain agonist is then defined as the ability to stabilize these specific conformations. This also implies that some 5-HT4 receptor agonists might only partially activate the library of potential signalling systems in a cell. Indeed, in HEK293 cells, 5-HT4(a) receptor activation triggers a strong [Ca2+]i increase that is dependent on the compound structure because benzamide-related compounds trigger higher responses than indoleamines.83

The existence of many C-terminal splice variants of the 5-HT4 receptor adds even further complexity. Several splice variant-specific alternative signal transduction cascades have been described in recombinant expression systems.83–87 The expression of different splice variants in different tissues (or species) might therefore contribute to differences in overall coupling in the different tissues. These variant and therefore tissue- or species-dependent differences in coupling are expected to influence the response of all agonists unless agonist-directed trafficking of the stimulus response occurs. Different agonists may then be able to activate different alternative signalling cascades through the different splice variants. In support of this, the calcium response observed with benzamidic compounds seems to be splice variant-specific, being only observed in 5-HT4(a) and not in 5-HT4(b).83

Agonist-induced effects.  Quite often, prucalopride is referred to as a full agonist while tegaserod is regarded as a partial agonist [see for instance, Refs (88,89)]. This clearly is an oversimplification and one really should avoid extrapolating the degree of agonism of a substance in a given tissue. For a start, there is the inherent difficulty in defining what a full agonist is.90 For reasons of simplicity we refer to full agonism when the agonists elicit the same maximal response as 5-HT, the endogenous ligand of the 5-HT4 receptor. When using this criterium in the literature, it is clear that both prucalopride and tegaserod have been reported as either full or partial agonist [see, e.g. Refs (21,39,69)].

These differences may originate from different grounds. First, a given agonist can behave as a full agonist in certain tissues, while it can express partial agonism in others. Indeed, the expression of partial vs full agonism by a drug largely depends on the system in which it is evaluated as the receptor density or coupling efficiency can differ. Some agonists will thus behave as partial agonists in low efficacy systems, while they behave as full agonists in high efficacy systems (e.g. with high receptor reserve). Therefore, based on differences in receptor density or coupling efficiency (which might be influenced by the nature of the splice variants), the degree of agonism of a given agonist in a given tissue can vary between species. Even within a single species, these properties can lead to a differential degree of agonism for a given substance between tissues.21 This may explain the many differences in benzamide-induced 5-HT4 receptor-mediated responses between different tissues or species.9

One example of a low efficacy system is the heart, which is reflected in the relatively low stimulation potency of 5-HT4 receptor agonists in this tissue. Because of its nature of low efficacy, this tissue provides a useful method for evaluating differences in the pharmacological profile of 5-HT4 receptor ligands. Substituted benzamides like renzapride, cisapride and metoclopramide or dihydrobenzofurancarboxamides like prucalopride, M0003 and M0004 behave as partial agonists at porcine sinoatrial and/or human right atrial 5-HT4 receptors91–93 while most tryptamines are full agonists compared with 5-HT.91,92 Prucalopride also acted as a partial agonist on the L-type Ca2+ current through 5-HT4 receptors in human atrial cells.94 Therefore, different organ-specific behaviour can be expected between these classes of compounds. Recently a porcine in vitro model has been developed to describe and explain organ-specific behaviour of 5-HT4 receptor agonists.21 In this model, the effects of 5-HT4 receptor agonists in a gastric assay (5-HT4 receptors on cholinergic neurones) were compared with their effects on the right and left atrium (low 5-HT4 receptor density 95). The model quantified the tissue-dependent partial agonism of prucalopride, M0003 and M0004 with prucalopride behaving as a full agonist in the gastric assay, and as a partial agonist in the left and right atrium whereas tegaserod was shown to be a full agonist in all assays.21 Tissue-selective expression of partial agonism might thus result in organ selectivity of a certain drug, as illustrated for prucalopride above. Interestingly, because of their low efficacy, benzamides and dihydrobenzofurancarboxamides actually antagonize the effects of exogenously administered 5-HT, as demonstrated for prucalopride, cisapride, renzapride and metoclopramide in human and/or porcine right atrium.91,93,96 A similar antagonizing and possibly protective behaviour might also occur vs endogenously released 5-HT as demonstrated in a porcine in vivo model in which renzapride reduced the 5-HT-induced tachycardia.97

Secondly, the situation is further complicated by the concept of agonist-directed trafficking of receptor signalling. This hampers the interpretation and extrapolation of in vitro tissue experiments since different agonists might couple to different effectors (which might be even more complicated by the differential expression of splice variants between tissues or species, see above) and consequently, the order of efficacy between agonists might be reversed in different tissues (or species). Several examples of reversed efficacy order between 5-HT4 receptor agonists can be found in the literature. In many systems where both agonists were tested, prucalopride has been described as the agonist with a lower efficacy compared with tegaserod,15,21,92,98 while in others prucalopride is classified as a full and tegaserod as a partial agonist.34,39 Interestingly, at the guinea-pig 5-HT4 receptor expressed in HEK293 cells, tegaserod behaved as a full agonist and prucalopride as a partial agonist. This order was reversed in the guinea-pig isolated colon longitudinal muscle myenteric plexus preparation (LMMPP).99 In addition, compared to 5-HT, cisapride has been shown to behave as a superagonist in mouse colliculi neurones, while in most GI preparations it is a partial agonist.9 Furthermore, the effect of prucalopride on substance P release in the guinea-pig colon (NK1-mediated rebound contraction) has not been observed with cisapride (30, personal observation). Although speculative, all these observations might result from the stabilization of a different conformational state of the 5-HT4 receptor by the different agonists.

Taken together, based on mixed drug-specific and tissue-dependent properties (e.g. the expression of partial agonism or agonist-specific signal transduction pathways), different agonists might differentially activate the multiple 5-HT4 receptor populations in the GI tract, thereby resulting in distinct overall effects in different tissues.

The tissue selectivity of agonists could also be affected by the degree of receptor desensitization. It is well established that 5-HT4 receptors can desensitize upon stimulation by an agonist as shown in recombinant expression systems, but also with native neuronal and non-neuronal receptors.100,101 It is often generalized that a partial agonist is less likely to induce desensitization.102 This general paradigm that the activity of an agonist and its ability to cause desensitization are coupled is based on studies on β2-adrenergic and muscarinic receptors demonstrating that partial agonists cause less desensitization than full agonists.103 However, for several 5-HT4 receptor agonists, the desensitization power was shown to be a function of the activation potency of the drugs rather than of their efficacy (partial agonistic character).100 The dependence on potency and not on efficacy reflects the influence of the agonists’ binding affinity. This is underscored by the fact that antagonists can also induce desensitization104 which even challenges the involvement of G protein activation and second messenger generation in the triggering of the desensitization. Indeed, for the motilin receptor it has been shown that desensitization can be decoupled from activation and desensitization is not only determined by potency.105 The existence of agonist-specific receptor conformations (see above), each unfolding and exposing different regions to the intracellular apparatus and each associated with specific function may render different desensitizing properties to two agonists despite similar activation potencies. Furthermore, since the desensitization process depends on the cellular environment of the 5-HT4 receptor,106 different agonists might induce different degrees of desensitization in different tissues, resulting in agonist-specific tissue selectivity; this also complicates extrapolation of data obtained in recombinant receptor systems. Above that, there are also splice variant-specific differences in desensitization.107,108 As shown in heterologous expression systems, 5-HT4(d) and 5-HT4(b) desensitize more rapidly than do 5-HT4(e) and 5-HT4(a). Therefore, different organ systems might exert different degrees of desensitization after stimulation with the same concentration of agonist if they express different 5-HT4 receptor splice variants. Differential effects on desensitization may have important therapeutic implications because desensitization can limit the biological effects of 5-HT4 agonists in vivo.

Differences with 5-HT at cardiac 5-HT4 receptors.  The QT prolonging effect of cisapride (see above) together with the cardiac location of 5-HT4 receptors did establish an atmosphere of confusion on the cardiac effects of 5-HT4 receptor agonists. Some authors still associate the cardiac effects of cisapride with cardiac 5-HT4 receptors.109 This is, however, completely wrong. 5-HT4 receptors are expressed in human atria and ventricles, albeit at very low densities.110 Therefore, the effects of many 5-HT4 receptor agonists (benzamides and dihydrobenzofurancarboxamides; see above) in the heart are particularly modest compared to 5-HT. These effects include an increase in contractile force (inotropic effect), a hastening of the onset of muscle relaxation (lusitropic effect) or for sinoatrial receptors an increase in beating rate (chronotropic effect). The very low efficacy compared with 5-HT is particularly relevant for the hypothetical association between 5-HT4 receptor activation and atrial arrhythmias, for which no evidence was found using renzapride and prucalopride96,111 but only using 5-HT at high concentrations and in specific in vitro conditions or preconditioned tissues. Prior treatment with ß-adrenoreceptor antagonists enhances the inotropic and arrhythmogenic potential of 5-HT by increasing the maximal response of ICaL to 5-HT112 without affecting expression levels of 5-HT4 receptors or L-type Ca2+ channel subunits.113 Interestingly, even in cells from β-adrenoreceptor antagonist-treated patients, prucalopride was devoid of any effect on arrhythmic activity.94 Proarrhythmic effects of 5-HT have been suggested to be related to Ca2+ overload. Prucalopride induces a smaller increase in L-type Ca2+ current compared with 5-HT and it would therefore appear unlikely that prucalopride could elicit atrial arrhythmias in patients with constipation.94,96 Prucalopride would actually block cardiac 5-HT4 receptors (see above), thereby even preventing arrhythmogenic effects of 5-HT.96

Cardiac 5-HT4 receptor-mediated responses quickly fade because of the action of phosphodiesterases (PDEs) which catalyse cAMP breakdown. Their inhibition is often needed to unmask the effects of 5-HT4 receptor agonists and 5-HT, as illustrated for the left atrium and the ventricles respectively.92,114 In addition to quenching of the 5-HT4 receptor-mediated effect, PDEs play a role in the compartmentation and targeting of the cAMP signal in the myocytes. Because of this mechanism, activation of different Gs-coupled receptors (e.g. β-adrenoreceptors and 5-HT4 receptors), both increasing cAMP levels, may lead to different effects on cardiac function. Because PDE inhibition greatly reduces cardiac compartmentation, the inotropic effect of the 5-HT4 receptor agonists in the presence of PDE inhibitors could be a direct consequence of the inhibition of PDE action (less cAMP breakdown) and/or, as compartmentation is lost, result from the more diffuse activation of cAMP substrates. Therefore, the physiological relevance of the experimental 5-HT4 receptor-mediated responses in the presence of a PDE inhibitor is questionable.

The large species-dependent heterogeneity in 5-HT receptor subtypes expressed in the heart limits the options to study all of this in a laboratory animal. Only pigs and monkeys have functional cardiac 5-HT4 receptors under physiological conditions. In addition, 5-HT4 receptor mRNA was detected in rat hearts, but a functional inotropic response only manifested after its upregulation following the induction of post-infarction congestive heart failure.115,116 Up as well as down regulation of 5-HT4 receptor mRNA expression levels associated with cardiac dysfunction has been demonstrated in human hearts.114,117

In vivo

Based on the arguments described above, in vivo differences between 5-HT4 receptor agonists can be expected. However, the complexity of the underlying mechanisms hampers a clear-cut interpretation. Some degree of tissue-specificity has been described for cisapride, mosapride and prucalopride. Mosapride selectively enhanced upper GI motility in conscious dogs.118 Cisapride accelerates gastric emptying and facilitates gastric accommodation, but has limited effects on colonic motility in humans.119,120 In contrast, prucalopride has been suggested to selectively stimulate colonic transit in healthy humans without altering gastric emptying or small bowel transit.121 However, the effect profile of cisapride might be influenced by 5-HT4 receptor-unrelated mechanisms (see above).

The in vivo effect of prucalopride in the canine colon supports a regional coordinated relaxation–contraction mechanism upon stimulation of 5-HT4 receptors.74 Prucalopride stimulates GI motility with a pronounced effect on the large bowel. In conscious dogs, it induces a pattern of enhanced motility in the proximal colon and reduced motility in the distal colon, facilitating propulsion of luminal contents. In addition, it clearly induces propulsive waves of contractions (colonic giant migrating contractions) starting in the proximal colon and progressing all the way to the anal sphincters, i.e. the canine equivalent of human large bowel mass movements.74 This typical ‘profile’ has not been observed with cisapride and tegaserod (Schuurkes, JAJ). Although tegaserod stimulates colonic transit, it does not induce giant migrating contractions in the canine colon.122

The physicochemical properties of the agonists might also underlie certain differences observed in vivo. It has been suggested that tegaserod exerts prokinetic effects in the lumen directly because it is poorly absorbed and is largely excreted unmetabolized in stool.12 Tonini123 suggested that antagonism at the inhibitory 5-HT4 autoreceptors on EC cells by ‘the partial 5-HT4 receptor agonist’ tegaserod might lead to enhanced release of 5-HT from EC cells which might contribute to the prokinetic effect of tegaserod.123 When higher concentrations of tegaserod diffuse into the intestinal wall, also the 5-HT4 receptors on the IPANS can be antagonized by the drug, decreasing the prokinetic effect. However, this hypothesis only holds if tegaserod is indeed a partial agonist at the 5-HT4 receptor in these two cell types but the experimental data are lacking to support this hypothesis and as discussed above, tegaserod has been shown to behave as a full agonist in several studies.


  1. Top of page
  2. Abstract
  3. Introduction
  4. The 5-HT4 receptor as a target for prokinetic drugs
  5. 5-HT4 receptor agonists
  6. Conclusion
  7. Acknowledgements
  8. References

5-HT4 receptor agonists have clear-cut prokinetic effects in the gut. These agonists differ in many aspects that are either related or unrelated to their interaction with 5-HT4 receptors. Differences that are unrelated to the 5-HT4 receptor, such as affinity at non-5-HT4 receptors, may influence the agent’s safety and overall benefit/risk profile. 5-HT4 receptor-related differences have an impact on the agonist’s overall activity in a given tissue. Together, these differences affect the therapeutic potential for the treatment of GI motility disorders. Based on available evidence, a highly selective 5-HT4 receptor agonist, such as prucalopride, may offer improved efficacy and safety to treat patients with impaired GI motility, such as severe chronic constipation.


  1. Top of page
  2. Abstract
  3. Introduction
  4. The 5-HT4 receptor as a target for prokinetic drugs
  5. 5-HT4 receptor agonists
  6. Conclusion
  7. Acknowledgements
  8. References

The authors are grateful to Luc Ver Donck and Lieve Heylen from Johnson & Johnson Pharmaceutical Research and Development (Beerse, Belgium) for the provision of the cisapride and tegaserod binding data.

Conflict of interests: The authors have no competing interests.


  1. Top of page
  2. Abstract
  3. Introduction
  4. The 5-HT4 receptor as a target for prokinetic drugs
  5. 5-HT4 receptor agonists
  6. Conclusion
  7. Acknowledgements
  8. References
  • 1
    Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002; 71: 53354.
  • 2
    Gershon MD. Review article: serotonin receptors and transporters -- roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther 2004; 20(Suppl 7): 314.
  • 3
    Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007; 132: 397414.
  • 4
    Jones BJ, Blackburn TP. The medical benefit of 5-HT research. Pharmacol Biochem Behav 2002; 71: 55568.
  • 5
    Dumuis A, Bouhelal R, Sebben M, Cory R, Bockaert J. A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol Pharmacol 1988; 34: 8807.
  • 6
    Dumuis A, Sebben M, Bockaert J. The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedebergs Arch Pharmacol 1989; 340: 40310.
  • 7
    Dumuis A, Sebben M, Bockaert J. BRL 24924: a potent agonist at a non-classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons. Eur J Pharmacol 1989; 162: 3814.
  • 8
    Bockaert J, Sebben M, Dumuis A. Pharmacological characterization of 5-hydroxytryptamine 4 (5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. Mol Pharmacol 1990; 37: 40811.
  • 9
    Langlois M, Fischmeister R. 5-HT4 receptor ligands: applications and new prospects. J Med Chem 2003; 46: 31944.
  • 10
    Bockaert J, Claeysen S, Compan V, Dumuis A. 5-HT4 receptors. Curr Drug Targets CNS Neurol Disord 2004; 3: 3951.
  • 11
    Cash BD, Chey WD. Review article: The role of serotonergic agents in the treatment of patients with primary chronic constipation. Aliment Pharmacol Ther 2005; 22: 104760.
  • 12
    Tonini M, Pace F. Drugs acting on serotonin receptors for the treatment of functional GI disorders. Dig Dis 2006; 24: 5969.
  • 13
    Schworer H, Ramadori G. Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro. Naunyn Schmiedebergs Arch Pharmacol 1998; 357: 54852.
  • 14
    Grider JR, Kuemmerle JF, Jin JG. 5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1p receptors on sensory CGRP neurons. Am J Physiol 1996; 270: G77882.
  • 15
    Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998; 115: 37080.
  • 16
    Grider JR. Neurotransmitters mediating the intestinal peristaltic reflex in the mouse. J Pharmacol Exp Ther 2003; 307: 4607.
  • 17
    Foxx-Orenstein AE, Kuemmerle JF, Grider JR. Distinct 5-HT receptors mediate the peristaltic reflex induced by mucosal stimuli in human and guinea pig intestine. Gastroenterology 1996; 111: 128190.
  • 18
    Liu M, Geddis MS, Wen Y, Setlik W, Gershon MD. Expression and function of 5-HT4 receptors in the mouse enteric nervous system. Am J Physiol Gastrointest Liver Physiol 2005; 289: G114863.
  • 19
    Briejer MR, Schuurkes JA. 5-HT3 and 5-HT4 receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon. Eur J Pharmacol 1996; 308: 17380.
  • 20
    Leclere PG, Lefebvre RA. Presynaptic modulation of cholinergic neurotransmission in the human proximal stomach. Br J Pharmacol 2002; 135: 13542.
  • 21
    De Maeyer JH, Prins NH, Schuurkes JA, Lefebvre RA. Differential effects of 5-hydroxytryptamine4 receptor agonists at gastric versus cardiac receptors: an operational framework to explain and quantify organ-specific behavior. J Pharmacol Exp Ther 2006; 317: 95564.
  • 22
    Prins NH, Van Der Grijn A, Lefebvre RA, Akkermans LM, Schuurkes JA. 5-HT(4) receptors mediating enhancement of contractility in canine stomach; an in vitro and in vivo study. Br J Pharmacol 2001; 132: 19417.
  • 23
    Amemiya N, Hatta S, Takemura H, Ohshika H. Characterization of the contractile response induced by 5-methoxytryptamine in rat stomach fundus strips. Eur J Pharmacol 1996; 318: 4039.
  • 24
    James AN, Ryan JP, Crowell MD, Parkman HP. Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation. Am J Physiol Gastrointest Liver Physiol 2004; 287: G6129.
  • 25
    Takada K, Sakurai-Yamashita Y, Yamashita K et al. Regional difference in correlation of 5-HT4 receptor distribution with cholinergic transmission in the guinea pig stomach. Eur J Pharmacol 1999; 374: 48994.
  • 26
    Takemura K, Takada K, Mameya S, Kaibara M, Taniyama K. Regional and functional differences of 5-hydroxytryptamine-receptor subtypes in guinea pig stomach. Jpn J Pharmacol 1999; 79: 419.
  • 27
    Takeda M, Tsukamoto K, Mizutani Y, Suzuki T, Taniyama K. Identification of SK-951, a novel benzofuran derivative, as an agonist to 5-HT4 receptors. Jpn J Pharmacol 1999; 79: 20312.
  • 28
    Prins NH, Akkermans LM, Lefebvre RA, Schuurkes JA. 5-HT(4) receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle. Br J Pharmacol 2000; 131: 92732.
  • 29
    Leclere PG, Prins NH, Schuurkes JA, Lefebvre RA. 5-HT4 receptors located on cholinergic nerves in human colon circular muscle. Neurogastroenterol Motil 2005; 17: 36675.
  • 30
    Briejer MR, Bosmans JP, Van Daele P et al. The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol 2001; 423: 7183.
  • 31
    LePard KJ, Ren J, Galligan JJ. Presynaptic modulation of cholinergic and non-cholinergic fast synaptic transmission in the myenteric plexus of guinea pig ileum. Neurogastroenterol Motil 2004; 16: 35564.
  • 32
    Xue L, Camilleri M, Locke GR, 3rd, et al. Serotonergic modulation of murine fundic tone. Am J Physiol Gastrointest Liver Physiol 2006; 291: G11806.
  • 33
    Briejer MR, Veen GJ, Akkermans LM, Lefebvre RA, Schuurkes JA. Cisapride and structural analogs selectively enhance 5-hydroxytryptamine (5-HT)-induced purinergic neurotransmission in the guinea pig proximal colon. J Pharmacol Exp Ther 1995; 274: 6418.
  • 34
    Cellek S, John AK, Thangiah R et al. 5-HT4 receptor agonists enhance both cholinergic and nitrergic activities in human isolated colon circular muscle. Neurogastroenterol Motil 2006; 18: 85361.
  • 35
    Baxter GS, Craig DA, Clarke DE. 5-Hydroxytryptamine4 receptors mediate relaxation of the rat oesophageal tunica muscularis mucosae. Naunyn Schmiedebergs Arch Pharmacol 1991; 343: 43946.
  • 36
    Komada T, Yano S. Pharmacological characterization of 5-Hydroxytryptamine-receptor subtypes in circular muscle from the rat stomach. Biol Pharm Bull 2007; 30: 50813.
  • 37
    Tuladhar BR, Costall B, Naylor RJ. Pharmacological characterization of the 5-hydroxytryptamine receptor mediating relaxation in the rat isolated ileum. Br J Pharmacol 1996; 119: 30310.
  • 38
    McLean PG, Coupar IM. Stimulation of cyclic AMP formation in the circular smooth muscle of human colon by activation of 5-HT4-like receptors. Br J Pharmacol 1996; 117: 2389.
  • 39
    Prins NH, Van Haselen JF, Lefebvre RA, Briejer MR, Akkermans LM, Schuurkes JA. Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle. Br J Pharmacol 1999; 127: 14317.
  • 40
    Smith AJ, Chappell AE, Buret AG, Barrett KE, Dong H. 5-Hydroxytryptamine contributes significantly to a reflex pathway by which the duodenal mucosa protects itself from gastric acid injury. FASEB J 2006; 20: 248695.
  • 41
    Tuo BG, Sellers Z, Paulus P, Barrett KE, Isenberg JI. 5-HT induces duodenal mucosal bicarbonate secretion via cAMP- and Ca2+ -dependent signaling pathways and 5-HT4 receptors in mice. Am J Physiol Gastrointest Liver Physiol 2004; 286: G44451.
  • 42
    Safsten B, Sjoblom M, Flemstrom G. Serotonin increases protective duodenal bicarbonate secretion via enteric ganglia and a 5-HT4-dependent pathway. Scand J Gastroenterol 2006; 41: 127989.
  • 43
    Kellum JM, Albuquerque FC, Stoner MC, Harris RP. Stroking human jejunal mucosa induces 5-HT release and Cl- secretion via afferent neurons and 5-HT4 receptors. Am J Physiol 1999; 277: G51520.
  • 44
    Burleigh DE, Borman RA. Short-circuit current responses to 5-hydroxytryptamine in human ileal mucosa are mediated by a 5-HT4 receptor. Eur J Pharmacol 1993; 241: 1258.
  • 45
    Budhoo MR, Harris RP, Kellum JM. The role of the 5-HT4 receptor in Cl- secretion in human jejunal mucosa. Eur J Pharmacol 1996; 314: 10914.
  • 46
    Hansen MB. ICS 205-930 reduces 5-methoxytryptamine-induced short-circuit current in stripped pig jejunum. Can J Physiol Pharmacol 1994; 72: 22732.
  • 47
    Borman RA, Burleigh DE. Human colonic mucosa possesses a mixed population of 5-HT receptors. Eur J Pharmacol 1996; 309: 2714.
  • 48
    Budhoo MR, Harris RP, Kellum JM. 5-Hydroxytryptamine-induced Cl- transport is mediated by 5-HT3 and 5-HT4 receptors in the rat distal colon. Eur J Pharmacol 1996; 298: 13744.
  • 49
    Talley NJ. New and emerging treatments for irritable bowel syndrome and functional dyspepsia. Expert Opin Emerg Drugs 2002; 7: 918.
  • 50
    Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil 2005; 17: 64353.
  • 51
    Schiller LR. New and emerging treatment options for chronic constipation. Rev Gastroenterol Disord 2004; 4(Suppl 2): S4351.
  • 52
    Buchheit KH, Gamse R, Giger R et al. The serotonin 5-HT4 receptor. 2. Structure-activity studies of the indole carbazimidamide class of agonists. J Med Chem 1995; 38: 23318.
  • 53
    Wallenborn J, Gelbrich G, Bulst D et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ 2006; 333: 324.
  • 54
    Valenzuela JE, Dooley CP. Dopamine antagonists in the upper gastrointestinal tract. Scand J Gastroenterol Suppl 1984; 96: 12736.
  • 55
    Parra A, Barron J, Sinibaldi J, Coria I, Espinosa de los Monteros A. Differences in the metoclopramide-induced prolactin release related to age at first full-term pregnancy or nulliparity. Hum Reprod 1997; 12: 2149.
  • 56
    Ohno K, Miyazawa S, Hashiguchi M et al. Establishing a comprehensive questionnaire for detecting drug-induced extrapyramidal symptoms. Yakugaku Zasshi 2003; 123: 8816.
  • 57
    Walkembach J, Bruss M, Urban BW, Barann M. Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers. Br J Pharmacol 2005; 146: 54352.
  • 58
    Talley NJ. Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. Aliment Pharmacol Ther 1992; 6: 27389.
  • 59
    Chey WD, Cash BD. Cilansetron: a new serotonergic agent for the irritable bowel syndrome with diarrhoea. Expert Opin Investig Drugs 2005; 14: 18593.
  • 60
    Chang L, Chey WD, Harris L, Olden K, Surawicz C, Schoenfeld P. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol 2006; 101: 106979.
    Direct Link:
  • 61
    Mohammad S, Zhou Z, Gong Q, January CT. Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol 1997; 273: H25348.
  • 62
    Rampe D, Roy ML, Dennis A, Brown AM. A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. FEBS Lett 1997; 417: 2832.
  • 63
    Potet F, Bouyssou T, Escande D, Baro I. Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-a-gogo K+ channel. J Pharmacol Exp Ther 2001; 299: 100712.
  • 64
    Busti AJ, Murillo JRJ, Cryer B. Tegaserod-induced myocardial infarction: case report and hypothesis. Pharmacotherapy 2004; 24: 52631.
  • 65
    Tack J, Vanden Berghe P, Coulie B, Janssens J. Sumatriptan is an agonist at 5-HT receptors on myenteric neurones in the guinea-pig gastric antrum. Neurogastroenterol Motil 2007; 19: 3946.
  • 66
    Gidener S, Apaydin S, Kupelioglu A, Guven H, Gelal A, Gure A. Serotonin causes acute gastric mucosal injury in rats, probably via 5HT1D receptors. Int J Exp Pathol 1995; 76: 23740.
  • 67
    Kaumann AJ, Parsons AA, Brown AM. Human arterial constrictor serotonin receptors. Cardiovasc Res 1993; 27: 2094103.
  • 68
    Thompson CA. Novartis suspends tegaserod sales at FDA’s request. Am J Health Syst Pharm 2007; 64: 1020.
  • 69
    Beattie DT, Smith JA, Marquess D et al. The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol 2004; 143: 54960.
  • 70
    Janssen P, Prins NH, Meulemans AL, Lefebvre RA. Smooth muscle 5-HT2A receptors mediating contraction of porcine isolated proximal stomach strips. Br J Pharmacol 2002; 137: 121724.
  • 71
    Glusa E, Pertz HH. Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT(2B) receptors. Br J Pharmacol 2000; 130: 6928.
  • 72
    Ishida T, Kawashima S, Hirata K, Yokoyama M. Nitric oxide is produced via 5-HT1B and 5-HT2B receptor activation in human coronary artery endothelial cells. Kobe J Med Sci 1998; 44: 5163.
  • 73
    Ismair MG, Kullak-Ublick GA, Blakely RD, Fried M, Vavricka SR. Tegaserod inhibits the serotonin transporter SERT. Digestion 2007; 75: 905.
  • 74
    Briejer MR, Prins NH, Schuurkes JA. Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil 2001; 13: 46572.
  • 75
    Buchheit KH, Gamse R, Giger R et al. The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site. J Med Chem 1995; 38: 232630.
  • 76
    Claeysen S, Joubert L, Sebben M, Bockaert J, Dumuis A. A single mutation in the 5-HT4 receptor (5-HT4-R D100(3.32)A) generates a Gs-coupled receptor activated exclusively by synthetic ligands (RASSL). J Biol Chem 2003; 278: 699702.
  • 77
    Lopez-Rodriguez ML, Benhamu B, Morcillo MJ et al. 5-HT(4) receptor antagonists: structure-affinity relationships and ligand-receptor interactions. Curr Top Med Chem 2002; 2: 62541.
  • 78
    Kenakin T. Collateral efficacy in new drug discovery. Trends Pharmacol Sci 2007; 28: 35961.
  • 79
    Kenakin T. Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol Sci 2007; 28: 40715.
  • 80
    Claeysen S, Sebben M, Becamel C, Parmentier ML, Dumuis A, Bockaert J. Constitutively active mutants of 5-HT4 receptors are they in unique active states? EMBO Rep 2001; 2: 617.
  • 81
    Joubert L, Claeysen S, Sebben M et al. A 5-HT4 receptor transmembrane network implicated in the activity of inverse agonists but not agonists. J Biol Chem 2002; 277: 2550211.
  • 82
    Baneres JL, Mesnier D, Martin A, Joubert L, Dumuis A, Bockaert J. Molecular characterization of a purified 5-HT4 receptor: a structural basis for drug efficacy. J Biol Chem 2005; 280: 2025360.
  • 83
    Pindon A, Van Hecke G, Van Gompel P, Lesage AS, Leysen JE, Jurzak M. Differences in signal transduction of two 5-HT4 receptor splice variants: compound specificity and dual coupling with Galphas- and Galphai/o-proteins. Mol Pharmacol 2002; 61: 8596.
  • 84
    Barthet G, Framery B, Gaven F et al. 5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated kinase pathway depends on Src activation but not on G protein or beta-arrestin signaling. Mol Biol Cell 2007; 18: 197991.
  • 85
    Norum JH, Hart K, Levy FO. Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a). J Biol Chem 2003; 278: 3098104.
  • 86
    Maillet M, Robert SJ, Cacquevel M et al. Crosstalk between Rap1 and Rac regulates secretion of sAPPalpha. Nat Cell Biol 2003; 5: 6339.
  • 87
    Robert S, Maillet M, Morel E et al. Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac. FEBS Lett 2005; 579: 113642.
  • 88
    Talley NJ. Drug therapy options for patients with irritable bowel syndrome. Am J Manag Care 2001; 7: S2617.
  • 89
    De Giorgio R, Barbara G, Furness JB, Tonini M. Novel therapeutic targets for enteric nervous system disorders. Trends Pharmacol Sci 2007; 28: 47381.
  • 90
    Black JW, Shankley NP. Interpretation of agonist affinity estimations: the question of distributed receptor states. Proc R Soc Lond B Biol Sci 1990; 240: 50318.
  • 91
    Medhurst AD, Kaumann AJ. Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium. Br J Pharmacol 1993; 110: 102330.
  • 92
    De Maeyer JH, Straetemans R, Schuurkes JA, Lefebvre RA. Porcine left atrial and sinoatrial 5-HT4 receptor-induced responses: fading of the response and influence of development. Br J Pharmacol 2006; 147: 14057.
  • 93
    Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ. A 5-HT4-like receptor in human right atrium. Naunyn Schmiedebergs Arch Pharmacol 1991; 344: 1509.
  • 94
    Pau D, Workman AJ, Kane KA, Rankin AC. Electrophysiological effects of prucalopride, a novel enterokinetic agent, on isolated atrial myocytes from patients treated with beta-adrenoceptor antagonists. J Pharmacol Exp Ther 2005; 313: 14653.
  • 95
    Kaumann AJ, Lynham JA, Brown AM. Labelling with [125I]-SB 207710 of a small 5-HT4 receptor population in piglet right atrium: functional relevance. Br J Pharmacol 1995; 115: 9336.
  • 96
    Krobert KA, Brattelid T, Levy FO, Kaumann AJ. Prucalopride is a partial agonist through human and porcine atrial 5-HT4 receptors: comparison with recombinant human 5-HT4 splice variants. Naunyn Schmiedebergs Arch Pharmacol 2005; 371: 4739.
  • 97
    Villalon CM, Den Boer MO, Heiligers JP, Saxena PR. Mediation of 5-hydroxytryptamine-induced tachycardia in the pig by the putative 5-HT4 receptor. Br J Pharmacol 1990; 100: 6657.
  • 98
    Jin JG, Foxx-Orenstein AE, Grider JR. Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors. J Pharmacol Exp Ther 1999; 288: 937.
  • 99
    Vickery RG, Mai N, Kaufman E et al. A comparison of the pharmacological properties of guinea-pig and human recombinant 5-HT4 receptors. Br J Pharmacol 2007; 150: 78291.
  • 100
    Ansanay H, Sebben M, Bockaert J, Dumuis A. Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons. Mol Pharmacol 1992; 42: 80816.
  • 101
    Ronde P, Ansanay H, Dumuis A, Miller R, Bockaert J. Homologous desensitization of 5-hydroxytryptamine4 receptors in rat esophagus: functional and second messenger studies. J Pharmacol Exp Ther 1995; 272: 97783.
  • 102
    Camilleri M. Review article: tegaserod. Aliment Pharmacol Ther 2001; 15: 27789.
  • 103
    Pittman RN, Reynolds EE, Molinoff PB. Relationship between intrinsic activities of agonists in normal and desensitized tissue and agonist-induced loss of beta adrenergic receptors. J Pharmacol Exp Ther 1984; 230: 6148.
  • 104
    Roettger BF, Ghanekar D, Rao R et al. Antagonist-stimulated internalization of the G protein-coupled cholecystokinin receptor. Mol Pharmacol 1997; 51: 35762.
  • 105
    Thielemans L, Depoortere I, Perret J et al. Desensitization of the human motilin receptor by motilides. J Pharmacol Exp Ther 2005; 313: 1397405.
  • 106
    Barthet G, Gaven F, Framery B et al. Uncoupling and endocytosis of 5-hydroxytryptamine 4 receptors. Distinct molecular events with different GRK2 requirements. J Biol Chem 2005; 280: 2792434.
  • 107
    Mialet J, Fischmeister R, Lezoualc’h F. Characterization of human 5-HT4(d) receptor desensitization in CHO cells. Br J Pharmacol 2003; 138: 44552.
  • 108
    Pindon A, Van Hecke G, Josson K et al. Internalization of human 5-HT4a and 5-HT4b receptors is splice variant dependent. Biosci Rep 2004; 24: 21523.
  • 109
    Ellidokuz E, Kaya D. The effect of metoclopramide on QT dynamicity: double-blind, placebo-controlled, cross-over study in healthy male volunteers. Aliment Pharmacol Ther 2003; 18: 1515.
  • 110
    Kaumann AJ, Lynham JA, Brown AM. Comparison of the densities of 5-HT4 receptors, beta 1- and beta 2-adrenoceptors in human atrium: functional implications. Naunyn Schmiedebergs Arch Pharmacol 1996; 353: 5925.
  • 111
    Sanders L, Lynham JA, Bond B, Del Monte F, Harding SE, Kaumann AJ. Sensitization of human atrial 5-HT4 receptors by chronic beta-blocker treatment. Circulation 1995; 92: 252639.
  • 112
    Pau D, Workman AJ, Kane KA, Rankin AC. Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic beta-adrenoceptor blockade. Br J Pharmacol 2003; 140: 143441.
  • 113
    Grammer JB, Zeng X, Bosch RF, Kuhlkamp V. Atrial L-type Ca2+ -channel, beta-adrenorecptor, and 5-hydroxytryptamine type 4 receptor mRNAs in human atrial fibrillation. Basic Res Cardiol 2001; 96: 8290.
  • 114
    Brattelid T, Qvigstad E, Lynham JA et al. Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure. Naunyn Schmiedebergs Arch Pharmacol 2004; 370: 15766.
  • 115
    Qvigstad E, Brattelid T, Sjaastad I et al. Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure. Cardiovasc Res 2005; 65: 86978.
  • 116
    Qvigstad E, Sjaastad I, Brattelid T et al. Dual serotonergic regulation of ventricular contractile force through 5-HT2A and 5-HT4 receptors induced in the acute failing heart. Circ Res 2005; 97: 26876.
  • 117
    Lezoualc’h F, Steplewski K, Sartiani L, Mugelli A, Fischmeister R, Bril A. Quantitative mRNA analysis of serotonin 5-HT4 receptor isoforms, calcium handling proteins and ion channels in human atrial fibrillation. Biochem Biophys Res Commun 2007; 357: 21824.
  • 118
    Mine Y, Yoshikawa T, Oku S, Nagai R, Yoshida N, Hosoki K. Comparison of effect of mosapride citrate and existing 5-HT4 receptor agonists on gastrointestinal motility in vivo and in vitro. J Pharmacol Exp Ther 1997; 283: 10008.
  • 119
    Talley NJ. Serotoninergic neuroenteric modulators. Lancet 2001; 358: 20618.
  • 120
    Krevsky B, Malmud LS, Maurer AH, Somers MB, Siegel JA, Fisher RS. The effect of oral cisapride on colonic transit. Aliment Pharmacol Ther 1987; 1: 293304.
  • 121
    Bouras EP, Camilleri M, Burton DD, McKinzie S. Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans. Gut 1999; 44: 6826.
  • 122
    Nguyen A, Camilleri M, Kost LJ et al. SDZ HTF 919 stimulates canine colonic motility and transit in vivo. J Pharmacol Exp Ther 1997; 280: 12706.
  • 123
    Tonini M. 5-Hydroxytryptamine effects in the gut: the 3, 4, and 7 receptors. Neurogastroenterol Motil 2005; 17: 63742.