The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders.

In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The cerebral distribution of this receptor is well conserved across species, with high densities in the basal ganglia, where they are expressed by GABAergic neurons. The 5-HT4 receptor is also present in the cerebral cortex, hippocampus, and amygdala, where they are carried by glutamatergic or cholinergic neurons. Outside the central nervous system, the 5-HT4 receptor is notably expressed in the gastrointestinal tract. The wide distribution of the 5-HT4 receptor undoubtedly contributes to its involvement in a plethora of functions. In addition, the modulation of this receptor influences the release of serotonin, but also the release of other neurotransmitters such as acetylcholine and dopamine. This is a considerable asset, as the modulation of the 5-HT4 receptor can therefore play a direct or indirect beneficial role in various disorders. One of the main advantages of this receptor is that it mediates a much faster antidepressant and anxiolytic action than classical selective serotonin reuptake inhibitors. Another major benefit of the 5-HT4 receptor is that its activation enhances cognitive performance, probably via the release of acetylcholine. The expression of the 5-HT4 receptor is also altered in various eating disorders, and its activation by the 5-HT4 agonist negatively regulates food intake. Additionally, although the cerebral expression of this receptor is modified in certain movement-related disorders, it is still yet to be determined whether this receptor plays a key role in their pathophysiology. Finally, there is no longer any need to demonstrate the value of 5-HT4 receptor agonists in the pharmacological management of gastrointestinal disorders.

Prucalopride and Bowel Function Post Gastrointestinal Surgery: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Prolonged postoperative ileus (PPOI) contributes to morbidity and prolonged hospitalization. Prucalopride, a selective 5-hydroxytryptamine receptor agonist, may enhance bowel motility. This review assesses whether the perioperative use of prucalopride compared to placebo is associated with accelerated return of bowel function post gastrointestinal (GI) surgery. METHODS: OVID, CENTRAL, and EMBASE were searched as of January 2024 to identify randomized controlled trials (RCTs) comparing prucalopride and placebo for prevention of PPOI in adult patients undergoing GI surgery. The primary outcomes were time to stool, time to flatus, and time to oral tolerance. The secondary outcomes were incidence of PPOI, length of stay (LOS), postoperative complications, adverse events, and overall costs. The Cochrane risk of bias tool for randomized trials and the Grading of Recommendations, Assessment, Development, and Evaluations framework were used. An inverse variance random effects model was used. RESULTS: From 174 citations, 3 RCTs with 139 patients in each treatment group were included. Patients underwent a variety of GI surgeries. Patients treated with prucalopride had a decreased time to stool (mean difference 36.82 hours, 95% CI 59.4 to 14.24 hours lower, I2 = 62%, low certainty evidence). Other outcomes were not statistically significantly different (very low certainty evidence). Postoperative complications and adverse events could not be meta-analyzed due to heterogeneity; yet individual studies suggested no significant differences (very low certainty evidence). DISCUSSION: Current RCT evidence suggests that prucalopride may enhance postoperative return of bowel function. Larger RCTs assessing patient important outcomes and associated costs are needed before routine use of this agent.

Clinical Outcomes Before and After Prucalopride Treatment: An Observational Study in Patients With Chronic Idiopathic Constipation in the United States.

INTRODUCTION: This real-world US-based claims study compared constipation-related symptoms and complications 6 months before and after prucalopride initiation in adults with chronic idiopathic constipation (CIC). METHODS: This observational, retrospective cohort analysis used the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental Database (January 2015-June 2020). Prucalopride-treated patients (≥18 years old) who had ≥1 constipation-related International Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) diagnosis code during the baseline or study period were included. The proportions of patients with constipation-related symptoms (abdominal pain, abdominal distension [gaseous], incomplete defecation, and nausea) and constipation-related complications (anal fissure and fistula, intestinal obstruction, rectal prolapse, hemorrhoids, perianal venous thrombosis, perianal/perirectal abscess, and rectal bleeding) were examined. Constipation-related symptoms and complications were identified using ICD-10-CM , ICD-10 - Procedure Coding System , or Current Procedural Terminology codes. Data were stratified by age (overall, 18-64 years, and ≥65 years). RESULTS: This study included 690 patients: The mean (SD) patient age was 48.0 (14.7) years, and 87.5% were women. The proportions of patients overall with constipation-related symptoms decreased 6 months after prucalopride initiation (abdominal pain [50.4% vs 33.3%, P < 0.001]; abdominal distension [gaseous] [23.9% vs 13.3%, P < 0.001]; and nausea [22.6% vs 17.7%, P < 0.01]; no improvements observed for incomplete defecation). Similarly, the proportions of patients overall with constipation-related complications decreased 6 months after prucalopride initiation (intestinal obstruction [4.9% vs 2.0%, P < 0.001]; hemorrhoids [10.7% vs 7.0%, P < 0.05]; and rectal bleeding [4.1% vs 1.7%, P < 0.05]). DISCUSSION: This study suggests that prucalopride may be associated with improved constipation-related symptoms and complications 6 months after treatment initiation.

Ergotamine Stimulates Human 5-HT4-Serotonin Receptors and Human H2-Histamine Receptors in the Heart.

Ergotamine (2'-methyl-5'α-benzyl-12'-hydroxy-3',6',18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus Claviceps purpurea. Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT1-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT4-serotonin receptors or H2-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H2-TG (mouse which exhibits cardiac-specific overexpression of the human H2-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT4-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT4-serotonin receptor). An amount of 10 µM ergotamine increased the left ventricular force of contraction in isolated retrogradely perfused spontaneously beating heart preparations of both 5-HT4-TG and H2-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergotamine 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, that were attenuated by 10 µM of the H2-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT4-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT4-serotonin receptors as well at human H2-histamine receptors. Ergotamine acts as an agonist on H2-histamine receptors in the human atrium.

A Review of the Cardiovascular Safety of Prucalopride in Patients With Chronic Idiopathic Constipation.

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.

Epithelial 5-HT4 Receptors as a Target for Treating Constipation and Intestinal Inflammation.

Because of their importance in the regulation of gut functions, several therapeutic targets involving serotonin-related proteins have been developed or repurposed to treat motility disorders, including serotonin transporter inhibitors, tryptophan hydroxylase blockers, 5-HT3 antagonists, and 5-HT4 agonists. This chapter focuses on our discovery of 5-HT4 receptors in the epithelial cells of the colon and our efforts to evaluate the effects of stimulating these receptors. 5-HT4 receptors appear to be expressed by all epithelial cells in the mouse colon, based on expression of a reporter gene driven by the 5-HT4 receptor promoter. Application of 5-HT4 agonists to the mucosal surface causes serotonin release from enterochromaffin cells, mucus secretion from goblet cells, and chloride secretion from enterocytes. Luminal administration of 5-HT4 agonists speeds up colonic motility and suppresses distention-induced nociceptive responses. Luminal administration of 5-HT4 agonists also decreases the development of, and improves recovery from, experimental colitis. Recent studies determined that the prokinetic actions of minimally absorbable 5-HT4 agonists are just as effective as absorbable compounds. Collectively, these findings indicate that targeting epithelial receptors with non-absorbable 5-HT4 agonists could offer a safe and effective strategy for treating constipation and colitis.

Chronic stimulation of the serotonergic 5-HT4 receptor modulates amyloid-beta-related impairments in synaptic plasticity and memory deficits in male rats.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory decline and impaired hippocampal synaptic plasticity. The serotonin 5-HT4 receptor is involved in learning and memory processes. This study explored the effects of chronic stimulation of 5-HT4R on cognition, memory, long-term potentiation (LTP), paired-pulse ratio (PPR), and neuronal apoptosis in a rat model of amyloid-beta (Aß)-induced AD. Thirty-five male Wistar rats were randomly divided into three groups as follows: the sham, Aß, and Aß + BIMU8 groups. Aß (6 µg/µl) was administrated by intracerebroventricular (icv) injection. The animals were treated with BIMU8 (1 µg/µL, ICV) as a 5-HT4R agonist for 30 days. Memory and behavioral changes were assessed by the passive avoidance learning, novel object recognition, open field, and elevated plus maze tests. Hippocampal synaptic plasticity was evaluated in the dentate gyrus (DG) in response to the stimulation applied to the perforant pathway. Furthermore, neuronal apoptosis was measured in the hippocampus. Data were analyzed by SPSS version 19 using one-way ANOVA, followed by Tukey's post hoc test. Aß induced memory deficits and neuronal loss and inhibited LTP induction. Aß also increased the normalized PPR. BIMU8 enhanced the slope of the field excitatory postsynaptic potential in LTP and improved cognition behavior. Paired-pulse inhibition or facilitation was not affected by LTP induction in Aß animals receiving the BIMU8. It can be concluded that the stimulation of the 5-HT4 receptor modulated the Aß-induced cognition and memory deficits, probably via a decrease in the hippocampal apoptotic neurons and an improvement in the hippocampal synaptic functions without involving its inhibitory interneurons.

Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task.

Cognitive deficits commonly accompany psychiatric disorders but are often underrecognised, and difficult to treat. The 5-HT4 receptor is a promising potential treatment target for cognitive impairment because in animal studies 5-HT4 receptor agonists enhance hippocampal-dependent memory processes. To date, there has been little work translating these effects to humans. We tested whether short-term administration of the 5-HT4 partial agonist, prucalopride, modified behavioural and neural (fMRI) memory processing in 44 healthy human volunteers using an experimental medicine model. We found that participants who had received six days of prucalopride treatment were significantly better at recalling previously seen neutral images and distinguishing them from new images. At a neural level, prucalopride bilaterally increased hippocampal activity and activity in the right angular gyrus compared with placebo. Taken together, these findings demonstrate the potential of 5-HT4-receptor activation for cognitive enhancement in humans, and support the potential of this receptor as a treatment target for cognitive impairment.

Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT4 Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease.

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.

Screening for Serotonin Receptor 4 Agonists Using a GPCR-Based Sensor in Yeast.

More than 30% of all pharmaceuticals target G-protein-coupled receptors (GPCRs). Here, we present a GPCR-based screen in yeast to identify ligands for human serotonin receptor 4 (5-HTR4). Serotonin receptor 4 agonists are used for the treatment of irritable bowel syndrome with constipation. Specifically, the HTR4-based screen couples activation of 5-HTR4 on the yeast cell surface to luciferase reporter expression. The HTR4-based screen has a throughput of one compound per second allowing the screening of more than a thousand compounds per day.

A population pharmacokinetic-pharmacodynamic model of YH12852, a highly selective 5-hydroxytryptamine 4 receptor agonist, in healthy subjects and patients with functional constipation.

YH12852, a novel, highly selective 5-hydroxytryptamine 4 (5-HT4 ) receptor agonist, is currently under development to treat patients with functional constipation. In this study, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model that adequately described the time courses of the plasma concentrations of YH12852 and its prokinetic effect as assessed by the Gastric Emptying Breath Test (GEBT) and to predict the prokinetic effect of YH12852 at higher doses through PD simulation. We used the plasma concentrations of YH12852 from patients with functional constipation and healthy subjects and the GEBT results from healthy subjects obtained from a phase I/IIa trial. The PK-PD modeling and covariate analysis were performed using NONMEM software. The prokinetic effect of YH12852 was described using a semimechanistic multicompartment PD model and an empirical model by Ghoos et al. A two-compartment model with first-order absorption adequately described the observed concentration-time profiles of YH12852. The semimechanistic multicompartment PD model and the revised Ghoos model with two slope parameters adequately described the observed kPCDt (the percent dose of 13 C excreted in the exhaled air at minute t after completing the test meal, multiplied by 1000) values. YH12852 accelerated gastric emptying even at low doses of 0.05-0.1 mg, and its prokinetic effect was greater in subjects suffering from more severe functional constipation. The PD simulation experiments revealed that the change from baseline in the half time for gastric emptying induced by YH12852 increased in a dose-dependent manner at 0.05-5 mg although the results at doses >0.1 mg were extrapolated. We also showed that the empirical Ghoos model is a special case of the general semimechanistic multicompartment PD model for gastric emptying.

Cardiovascular effects of metoclopramide and domperidone on human 5-HT4-serotonin-receptors in transgenic mice and in human atrial preparations.

It is unclear whether metoclopramide and domperidone act on human cardiac serotonin 5-HT4-receptors. Therefore, we studied transgenic mice that only express the human 5-HT4 receptor in cardiomyocytes in the atrium and in the ventricle (5-HT4-TG), their wild type-littermates (WT) and isolated human atrial preparations. We found that only metoclopramide but not domperidone enhanced the force of contraction in left atrial preparations (pEC50 = 6.0 ± 0.1; n = 7) from 5-HT4-TG, isolated spontaneously beating right atrial preparations (pEC50 = 6.1 ± 0.1; n = 7) from 5-HT4-TG, Langendorff perfused hearts from 5-HT4-TG, living 5-HT4-TG and human right atrial muscle preparations obtained during bypass surgery of patients suffering from coronary heart disease. The maximum inotropic effect of metoclopramide was smaller (81 ± 2%) than that of 5-HT on the left atria from 5-HT4-TG. The maximum increase in the beating rate due to metoclopramide was 93 ± 2% of effect of 5-HT on right atrial preparations from 5-HT4-TG. Metoclopramide and domperidone were inactive in WT. We found that metoclopramide but not domperidone increased the phosphorylation state of phospholamban in the isolated perfused hearts or muscle strips of 5-HT4-TG, but not in WT. Metoclopramide, but not domperidone, shifted the positive inotropic or chronotropic effects of 5-HT in isolated left atrial and right atrial preparations from 5-HT4-TG dextrally, resp., to higher concentrations: the pEC50 of 5-HT for increase in force was in the absence of metoclopramide 8.6 ± 0.1 (n = 5) versus 8.0 ± 0.3 in the presence of 1 µM metoclopramide (n = 5; P < 0.05); and the beating rate was 7.8 ± 0.2 (n = 7) in the absence of metoclopramide versus 7.2 ± 0.1 in the presence of 1 µM metoclopramide (n = 6; P < 0.05). These results suggested that metoclopramide had an antagonistic effect on human cardiac 5-HT4 receptors. In summary, we showed that metoclopramide, but not domperidone, was a partial agonist at human cardiac 5-HT4-receptors.

Investigation of cardiorespiratory effects of the selective 5-HT4 agonist BIMU-8 in etorphine-immobilised goats (Capra aegagrus hircus) in a randomized, blinded and controlled trial.

BACKGROUND: Opioid-induced respiratory compromise remains a significant challenge in etorphine-immobilised wildlife. Serotonergic agonists offer a potential avenue for preventing or treating opioid-induced respiratory compromise. We therefore aimed to determine whether the selective 5-hydroxytryptamine receptor 4 (5-HT4) agonist, BIMU-8, reverses opioid-induced respiratory compromise in etorphine-immobilised goats. METHODS: Seven healthy adult goats were immobilised with etorphine, then treated with BIMU-8 or sterile water 5 minutes later in a randomised, prospective cross-over study. Cardiorespiratory variables were measured at 1-minute intervals from 4 minutes before etorphine to 15 minutes after its administration. Arterial blood gas analyses were also performed before and after etorphine administration and the respective treatments. RESULTS: Intravenous injection of BIMU-8 attenuated etorphine-induced respiratory compromise, as indicated by improvements, compared to baseline and between treatments, in respiratory rate (fR ), peripheral arterial blood oxygen saturation (SpO2 ), partial pressure of arterial oxygen (PaO2 ) and the alveolar-arterial oxygen partial pressure gradient (P(A-a)O2 ). BIMU-8 caused an increase in heart rate and a temporary decrease in arterial blood pressure. Mild movements and slight muscle spasm occurred but BIMU-8 did not reverse immobilisation. CONCLUSION: Our results indicate that BIMU-8 may be a potential drug candidate for the treatment, or prevention, of etorphine-induced respiratory compromise in immobilised ungulates.

Understanding the Molecular Basis of 5-HT4 Receptor Partial Agonists through 3D-QSAR Studies.

Alzheimer's disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT4 receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT4 receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures' field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R2training = 0.821, and for the test set R2test = 0.667, while for Gaussian-field QSAR the training and the test were R2training = 0.898 and R2test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of Q2LOO = 0.804 and Q2LOO = 0.886 for force- and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT4 partial agonists with potential biological activity (pEC50 8.209-9.417 for force-field QSAR and 9.111-9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT4 partial agonists.

First-in-Human Studies to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Novel 5-HT4 Partial Agonist, SUVN-D4010, in Healthy Adult and Elderly Subjects.

BACKGROUND AND OBJECTIVE: SUVN-D4010 is a novel, potent, highly selective 5-HT4 partial agonist intended for the treatment of cognitive disorders. The objective of the clinical study was to characterize the safety, tolerability, and pharmacokinetics of SUVN-D4010 in healthy adults after single and multiple doses, and to evaluate the effect of food, sex, and age on the pharmacokinetics. METHODS: Single-ascending dose and multiple-ascending dose studies for 14 days were conducted in healthy adults using a randomized, double-blind design. The effects of food, sex, and age on SUVN-D4010 pharmacokinetics (25 mg single dose) were evaluated using an open-label, two-period, randomized, fed and fasted, crossover design. Pharmacokinetics and safety assessments were conducted throughout the study. RESULTS: SUVN-D4010 at a single dose up to 45 mg and multiple doses up to 40 mg once daily was found to be safe and well tolerated in healthy adults. The most frequently reported adverse events were headache and nausea. SUVN-D4010 exposure was dose proportional across the tested doses. Steady state was achieved on day 2 after once-daily dosing for 14 days. Food had no significant effect on the exposures but an increase in median time to attain the maximum plasma concentration (tmax) from 2 h in a fasted state to 3.5 h in fed state was observed. The maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of SUVN-D4010 was 37% and 39%, respectively, lower in adult females compared to males following administration of a single 25 mg dose. In the elderly population, Cmax and AUC of SUVN-D4010 were 42% and 37%, respectively, lower compared to adult males following administration of a single 25 mg dose. SUVN-D4010 was well tolerated and safe in elderly subjects (≥ 65 years) following a single 25 mg dose. CONCLUSION: SUVN-D4010 was found to be safe and well tolerated in healthy human subjects. SUVN-D4010 followed linear pharmacokinetics across the dose range. Accumulation was in the range of 1.3- to 1.4-fold after multiple dosing. Renal excretion is not the major route of elimination. Food had no effect on the exposures but increased the tmax of SUVN-D4010. Exposures were lower in females and elderly subjects suggesting sex and age effects on the pharmacokinetics of SUVN-D4010 and possible dose adjustment in these populations. SUVN-D4010 was well tolerated and safe in elderly subjects after a single dose. Clinical trial identifiers: NCT02575482 and NCT03031574.

Colonic 5-HT4 receptors are targets for novel prokinetic drugs.

5-HT4 receptors are G protein-coupled receptors that link to the stimulatory protein Gs which activates adenylate cyclase to increase intracellular cyclic AMP which then activates protein kinase A (PKA). 5-HT4 receptors are expressed by neurons in the central and peripheral nervous systems especially the enteric nervous system (ENS). In general, 5-HT4 receptors are stimulatory and their activation in the ENS enhances neurotransmitter release and propulsive motility patterns. 5-HT4 receptors are expressed by enterochromaffin (EC) cells, Goblet cells, and most enteric neurons. The study by Konen and colleagues in this issue of Neurogastroenterology and Motility features two novel 5-HT4 receptor agonists (5-HT4 -LA1 and 5-HT4 -LA-2) that are not absorbed from the gastrointestinal tract of mice and act locally in the colonic mucosa to stimulate propulsive motility. The authors show that 5-HT4 -LA1 and 5-HT4 -LA2 were not absorbed from the colon and that both drugs stimulated colonic transit when administered by gavage. Both agonists stimulated colonic glass bead expulsion, and 5-HT4 LA1 activation stimulated fecal output and increased fecal water content. These effects were detected in young and aged mice. 5-HT4 receptors were also localized to the epithelium of the human duodenum, ileum, and colon. These studies highlight novel 5-HT4 receptor agonists that have prokinetic actions on the GI tract. These drugs are not absorbed and act locally in the gut mucosa to stimulate propulsive motility while minimizing access to systemic 5-HT4 receptors and avoiding potential unwanted side effects.

The effect of prucalopride on gastric sensorimotor function and satiation in healthy volunteers.

BACKGROUND: Gastric motor function alterations have been implicated in the pathogenesis of functional dyspepsia with postprandial distress syndrome (PDS). Prucalopride, a 5-TH4 agonist, is known to stimulate gastrointestinal motility. We aimed to evaluate the effect of prucalopride on gastric sensorimotor function in healthy subjects (HV). METHODS: Barostat and intragastric pressure (IGP) measurements were performed in 17 HV (59% females, age 29.4 ± 2.7 y) after treatment with placebo or prucalopride (2 mg) (single-blind cross-over). Isobaric stepwise distensions and gastric sensations were assessed to determine gastric compliance and sensitivity. Gastric accommodation (GA) with the barostat was quantified before and after ingestion of 200 ml of a nutrient drink (ND). GA measured by IGP was quantified as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation (60 ml/min). KEY RESULTS: Prucalopride did not affect barostat assessed gastric compliance or sensitivity. No differences were observed in GA after prucalopride. During the barostat study, 10 min after the meal, 7 HVs reported significantly higher ratings for nausea after prucalopride (p < 0.001), and vomiting was induced in 4 of the HVs. A positive correlation was observed between the delta mean perception of nausea with the delta mean increase of intra-balloon volume before and after meal ingestion (r = 0.37, p = 0.03). During IGP measurements, no effect on nutrient tolerance was observed and increased cramp severity scores were observed which were associated with a significant increase of distal IGP (r = 0.78, p < 0.0001). CONCLUSIONS & INFERENCES: Prucalopride does not enhances gastric accommodation but it might increase sensitivity to gastric distention. Furthermore, the increase in sensitivity seems to be related to an increase in nausea with distension. Clinicaltrials.gov: NCT04429802.

The effect of 5-HT4 serotonin receptors in the CA3 hippocampal region on D-AP5-induced anxiolytic-like effects: Isobolographic analyses.

Increasing evidence shows the close relationship between hippocampal glutamatergic and serotonergic systems through the modulation of behavioral responses. This study aimed to investigate the possible involvement of 5-HT4 receptors in the CA3 hippocampal region in anxiolytic-like effects induced by D-AP5 (a competitive antagonist of the glutamate NMDA [N-Methyl-D-aspartate] receptor). Male Wistar rats were placed in the elevated plus maze (EPM) apparatus that is used to assess anxiety-related behaviors, and the percentages of open arm time (%OAT) and open arm entries (%OAE) which are associated with anxiety-related behaviors were measured. The close arm entries (CAE) which is correlated with locomotor activity was also evaluated. The results showed that, intra-CA3 injection of D-AP5 (0.4 µg/rat), RS67333 (1.2 µg/rat; a 5-HT4 receptor agonist), and RS23597-190 (1.2 µg/rat; a 5-HT4 receptor antagonist) increased %OAT and %OAE, indicating the anxiolytic-like effect of these drugs. Also, only RS23597-190 (1.2 µg/rat) decreased CAE. Intra-CA3 injection of sub-threshold dose of RS67333 (0.012 µg/rat) or RS23597-190 (0.012 µg/rat), 5 min before the injection of D-AP5 (0.2 µg/rat) increased %OAT, indicating potentiating the anxiolytic-like effect of D-AP5. The isobolographic analyses also showed the additive or synergistic anxiolytic-like effect of intra-CA3 co-administration of D-AP5 with RS67333 or RS23597-190, respectively. In conclusion, CA3 5-HT4 receptors are involved in D-AP5-induced anxiolytic-like behaviors in rats.