5-HT4 Receptor Agonist Research Articles

Use of prucalopride in adults with chronic idiopathic constipation

ABSTRACTIntroduction: Prucalopride is a selective 5-HT4 receptor agonist with colonic prokinetic activity. It was recently approved by the FDA for the treatment of chronic idiopathic constipation. Before this approval, there were limited options to improve colonic motility in the treatment of chronic idiopathic constipation.Areas covered: We systematically searched PubMed, Embase, ClinicalTrials.gov, and international conference presentations, and we reviewed all studies that evaluated prucalopride for the treatment of chronic idiopathic constipation in adults. In this review, we discuss the pharmacokinetics, pharmacodynamics, receptor interactions, phase I-IV clinical trials, and safety outcomes of prucalopride in adults, including the elderly.Expert opinion: Prucalopride is an effective agent to improve colonic motility, decrease colonic transit time, and increase complete spontaneous bowel movements in patients with chronic idiopathic constipation. Unlike previously available 5-HT4 receptor agonists such as cisapride and tegaserod, prucalopride does not interact with the cardiac hERG potassium channels or other serotonergic receptors in blood vessels and is not associated with an increase in major adverse cardiovascular events. Additionally, prucalopride has demonstrated promise in the treatment of gastroparesis, post-operative ileus, and opioid-induced constipation. Prucalopride directly stimulates colonic motility, differentiating it from all other medications (exclusively osmotic or chloride secretagogues) approved for chronic constipation in the last decade.

Cannabidiol Affects the Bezold-Jarisch Reflex via TRPV1 and 5-HT3 Receptors and Has Peripheral Sympathomimetic Effects in Spontaneously Hypertensive and Normotensive Rats.

Cannabidiol (CBD) is a nonpsychotropic constituent of Cannabis sativa L. It is suggested to be useful in hypertension. Under in vitro conditions, it activates vanilloid TRPV1 and inhibits serotonin 5-HT3 receptors, i.e., receptors involved in the Bezold-Jarisch reflex stimulation. The aim of our study was to compare the cardiovascular effects of CBD in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Experiments were performed on conscious, urethane-anesthetized, and pithed rats. In pithed SHR and WKY, CBD increased heart rate (HR) and systolic blood pressure (SBP) and decreased diastolic BP (DBP) in a manner insensitive to adrenalectomy. Propranolol strongly impaired the CBD-induced increases in HR and SBP without affecting the decreases in DBP. Desipramine also reduced the CBD-induced effects on HR and SBP and further increased its effects on DBP. In anesthetized rats, bolus i.v. injection of single doses of CBD induced short-lasting decreases in HR, SBP, and DBP, stronger in SHR than in WKY and prevented by bilateral vagotomy. The CBD-induced fall in HR but not in BP was diminished by the TRPV1 receptor antagonist capsazepine and almost completely abolished if CBD was re-injected after previous administration. CBD reduced the Bezold-Jarisch reflex elicited by the 5-HT3 receptor agonist phenylbiguanide but not that evoked by the TRPV1 agonist capsaicin. In conscious rats, CBD did not affect cardiovascular parameters. In isolated left atria, CBD decreased contractile force. Conclusions: Cannabidiol (1) induces the Bezold-Jarisch reflex likely via TRPV1 receptors (which undergo tachyphylaxis) more markedly in SHR than in WKY; (2) inhibits the Bezold-Jarisch reflex induced by activation of 5-HT3 but not TRPV1 receptors; (3) has peripheral sympathomimetic, (4) vasodilatory, and (5) negative inotropic effects. The above properties of CBD should be taken under consideration when CBD is used for therapeutic purposes.

Activation and blockade of dorsal hippocampal Serotonin6 receptors regulate anxiety-like behaviors in a unilateral 6-hydroxydopamine rat model of Parkinson’s disease

ABSTRACTObjectives: This study aimed to investigate the effect of serotonin6 (5-HT6) receptors in the dorsal hippocampus (dHip) on the regulation of Parkinson’s disease (PD)-associated anxiety.Methods: We examined whether intra-dHip injection of both 5-HT6 receptor agonist and antagonist was involved in the regulation of anxiety-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle by the open-field and elevated plus maze (EPM) tests. Four weeks after injection of 6-OHDA, the concentrations of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in relative related brain regions were measured by reverse-phase high-performance liquid chromatography.Results: In sham-operated rats, intra-dHip injection of both 5-HT6 receptor agonist WAY208466 (3 and 6 µg/rat) and antagonist SB258585 (4 µg/rat) increased the percentage of time spent in the center area in the open-field test and percentages of open arm entries and open arm time in EPM test, indicating that induced anxiolytic effects. In the lesioned rats, WAY208466 (1.5, 3 and 6 µg/rat) produced anxiolytic responses, whereas SB258585 (2 and 4 µg/rat) produced anxiogenic effects. Neurochemical results showed that intra-dHip injection of WAY208466 (6 µg/rat) decreased NA level in the amygdala, and SB258585 (4 µg/rat) increased DA levels in the dHip and vHip in sham-operated rats, whereas WAY208466 increased DA levels in the dHip, vHip, and amygdala in the lesioned rats.Discussion: dHip 5-HT6 receptors are involved in the regulation of anxiety-like behaviors, which may be mediated through different neurochemical mechanisms, and the dHip is an important site involved in these effects.Abbreviation: PD: Parkinson’s disease;6-OHDA: 6-hydroxydopamine; dHip: dorsal hippocampus; vHip: ventral hippocampus; 5-HT: serotonin; MFB: medial forebrain bundle; DA: dopamine; NA: noradrenaline; EPM: elevated plus-maze; GABA: gamma-aminobutyric acid; BLA: basolateral amygdala

Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited.

Metoclopramide is primarily a dopamine receptor antagonist, with 5HT3 receptor antagonist and 5HT4 receptor agonist activity, and used as an antiemetic and gastroprokinetic since almost 50years. Regulatory authorities issued restrictions and recommendations regarding long-term use of the drug at oral doses exceeding 10mg 3-4 times daily because of the risk for development of tardive dyskinesia. The aim of our study was to review mechanism(s) of action and pharmacokinetic-pharmacodynamic properties of metoclopramide, as well as the risk of metoclopramide-induced tardive dyskinesia, factors that may change drug exposure in humans, and to summarize the clinical context for appropriate use of the drug. A PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: drug-drug interaction, gastroparesis, metoclopramide, natural history, pharmacokinetics, pharmacodynamics, drug-drug interaction, outcome, risk factors, tardive dyskinesia. Data show that the risk of tardive dyskinesia from metoclopramide is low, in the range of 0.1% per 1000 patient years. This is far below a previously estimated 1%-10% risk suggested in treatment guidelines by regulatory authorities. High-risk groups are elderly females, diabetics, patients with liver or kidney failure, and patients with concomitant antipsychotic drug therapy, which reduces the threshold for neurological complications. The risk of tardive dyskinesia due to metoclopramide is far below approximated numbers in treatment guidelines. This risk and the influence of known risk factors should be considered when starting a course of metoclopramide for treatment of gastroparesis.

Intraluminal prucalopride increases propulsive motor activities via luminal 5-HT4 receptors in the rabbit colon.

Activating luminal 5-HT4 receptors results in the release of 5-HT from enterochromaffin cells into the lamina propria to modulate colonic motility. Our aim was to evaluate characteristics of colonic motor patterns involved in the prokinetic effects of intraluminal prucalopride in the rabbit colon. Colonic motor patterns were studied ex vivo using simultaneous spatiotemporal diameter mapping and pressure sensing. Intraluminal prucalopride and intraluminal exogenous5-HT strongly evoked or enhanced the colonic motor complex at all levels of excitation beginning with generation of clusters of fast propagating contractions (FPCs), then development of long-distance contractions (LDCs) within the clusters, and finally forceful LDCs as the highest level of excitation. Intraluminal prucalopride and intraluminal exogenous5-HT stimulated propulsive motor activity in a dose-dependent and antagonist-sensitive manner by increasing the contraction amplitude, intraluminal pressure, frequency, velocity, and degree of propagation of the colonic motor complex. Activating mucosal 5-HT4 receptors via intraluminal prucalopride or 5-HT increases propulsive motor activity in a graded manner; that is, dependingon starting conditions, amplitudes or frequencies of an activity may increase or a new pattern may be initiated. Our data support further studies into delivering 5-HT4 receptor agonists via colon-targeted drug delivery systems and studies into the role of luminal 5-HT as an essential requirement for normal colon motor pattern generation.

Activation and blockade of serotonin4 receptors in the lateral habenula improve working memory in unilateral 6-hydroxydopamine-lesioned Parkinson’s rats

ABSTRACTObjective: The aim of the present study was to investigate the effects and mechanism of 6-hydroxydopamine (6-OHDA) lesions and serotonin 4 (5-HT4) receptors in the lateral habenula (LHb) on Parkinson’s disease (PD) related working memory. Methods: The working memory was measured by the T-maze rewarded alternation test in sham rats and rats with unilateral 6-OHDA lesions of substantia nigra pars compacta (SNc). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by neurochemistry.Results: The results showed that 6-OHDA lesions of the SNc induced working memory impairment. Intra-LHb injection of 5-HT4 receptor agonist BIMU-8 (2, 4 or 8 μg) and antagonist GR113808 (1, 3.3 or 10 μg) improved the working memory only in the lesioned rats. Intra-LHb injection of BIMU-8 (8 μg) significantly increased DA levels in the medial prefrontal cortex, dorsal hippocampus and amygdala in the lesioned rats but not in sham rats. BIMU-8 did not change NA and 5-HT levels in the related brain regions in both sham and lesioned rats. Intra-LHb injection of GR113808 (10 μg) changed DA, NA and 5-HT levels in related brain regions in both sham and the lesioned rats. In addition, the 5-HT4 receptor-positive neurons in the LHb increased significantly in the lesioned rats.Conclusion: These findings suggested that unilateral lesions of the SNc induced working memory impairment and up-regulation of 5-HT4 receptors in the LHb. Activation and blockade of LHb 5-HT4 receptors improved working memory, that were related to the change of monoamines levels.Abbreviation: 6-OHDA: 6-hydroxydopamine; serotonin:5-HT; LHb: lateral habenula; PD: Parkinson’s disease; SNc: substantia nigra pars compacta; DA: dopamine; NA: noradrenaline

Effects of Motilin Receptor Agonists and Ghrelin in Human motilin receptor Transgenic Mice.

Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a μ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.

Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers

The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmax = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.

Cross state-dependency of learning between 5-HT1A and/or 5-HT7 receptor agonists and muscimol in the mouse dorsal hippocampus.

Dysfunction of the serotonergic and GABAergic systems in cognitive disorders has been revealed. Understanding the neurobiological mechanisms of drug-associated learning and memory formation may help treatment of cognitive disorders. The aim of the present study was to investigate: 1) 8-OH-DPAT (5-HT1A agonist), AS19 (5-HT7 agonist) and muscimol (GABA-A agonist) on memory retrieval and state of memory, 2) cross state-dependent learning between 8-OH-DPAT and/or AS19 and muscimol. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended sites of injection. A single-trial step-down inhibitory avoidance task was used for the evaluation of memory retrieval and state of memory. Post-training and/or pre-test 8-OH-DPAT, AS19 and muscimol induced amnesia. Pre-test microinjection of the same doses of 8-OH-DPAT, AS19 and muscimol reversed the post-training 8-OH-DPAT-, AS19- and muscimol-induced amnesia, respectively. This event has been named state-dependent learning (SDL). The amnesia induced by 8-OH-DPAT was reversed by muscimol and induced 8-OH-DPAT SDL. The amnesia induced by muscimol was reversed by 8-OH-DPAT and induced muscimol SDL. The amnesia induced by AS19 was reversed by muscimol and induced AS19 SDL. The amnesia induced by muscimol was reversed by AS19 and induced muscimol SDL. Pre-test administration of a selective GABA-A receptor antagonist, bicuculline, 5 min before muscimol, 8-OH-DPAT and AS19 dose-dependently inhibited muscimol-, 8-OH-DPAT- and AS19-induced SDL, respectively. The results strongly revealed a cross SDL among 8-OH-DPAT and/or AS19 and muscimol in the dorsal hippocampal CA1 regions.

Protective effect of 5-HT7 receptor activation against glutamate-induced neurotoxicity in human neuroblastoma SH-SY5Y cells via antioxidative and antiapoptotic pathways

Serotonin exerts anti-inflammatory, antioxidant and antiapoptotic effects through 5-HT7 receptors. The present study determined the role of 5-HT7 receptors in glutamate-induced neurotoxicity by using human SH-SY5Y neuroblastoma cells. The cells were pretreated with different concentrations of 5-HT7 receptor agonist LP44 and antagonist SB269970 for 60 min, followed by treatment with glutamate. Cell proliferation was measured using xCELLigence system. Treatment with all the concentrations of LP44 significantly protected the cells from the toxic effects of glutamate after 24, 48 and 72 h. Although 5-HT7 receptor expression was significantly upregulated in glutamate-treated cells, it was downregulated in LP44-pretreated cells. Furthermore, LP44 treatment significantly decreased malondialdehyde levels and increased superoxide dismutase activities and glutathione levels. Moreover, LP44 treatment significantly decreased tumor necrosis factor alpha (TNF-α) levels and inhibited caspase 3 and caspase 9 mRNA expression. In contrast, SB269970 treatment exerted an insignificant effect on oxidative stress, inflammation and apoptosis. These findings suggest that exogenous stimulation of the 5-HT7 receptors may be protective in glutamate-induced neurotoxicity and that 5-HT7 receptor agonists can be used as therapeutic agents for preventing glutamate-induced neurological disorders.

Potentiation of the glycine response by serotonin on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice.

The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current (IGly). Firstly, we examined with a 5-HT1 receptor agonist (8-OH-DPAT, 5-HT1/7 agonist, co-applied with SB-269970, 5-HT7 antagonist) and antagonist (WAY-100635), but 5-HT1 receptor agonist did not increase IGly and in the presence of 5-HT1 antagonist, the potentiation of 5-HT on IGly still happened. However, an agonist (α-methyl-5-HT) and antagonist (ketanserin) of the 5-HT2 receptor mimicked and inhibited the enhancing effect of 5-HT on IGly in the SG neurons, respectively. We also verified the role of the 5-HT7 receptor by using a 5-HT7 antagonist (SB-269970) but it also did not block the enhancement of 5-HT on IGly. Our study demonstrated that 5-HT facilitated IGly in the SG neurons of the Vc through the 5-HT2 receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.

Rapid anxiolytic effects of 5-HT4 receptor agonist involves prefrontal cortex-brainstem neural circuit recruitment

Rapid anxiolytic effects of 5-HT4 receptor agonist involves prefrontal cortex-brainstem neural circuit recruitment

SR 57227A is a partial agonist/partial antagonist of 5-HT3 receptor and inhibits subsequent 5-HT- or SR 57227A-induced 5-HT3 receptor current

The serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptors are transmembrane ligand-gated ion channels. Although several 5-HT3 receptor agonists have been used as preclinical tools, SR 57227A is the most commonly used 5-HT3 receptor agonist with the ability to cross the blood brain barrier. However, the precise pharmacological profile of SR 57227A remains unclear. Therefore, we examined the pharmacological profile of SR 57227A at the 5-HT3A and 5-HT3AB receptors. We microinjected Xenopus laevis oocytes with human 5-HT3A complementary RNA (cRNA) or a combination of human 5-HT3A and human 5-HT3AB cRNA and performed two electrode voltage clamp recordings of 5-HT3A and 5-HT3AB receptor current in the presence of SR 57227A. Results showed that SR 57227A acts as partial agonist/partial antagonist at the 5-HT3 receptor. Interestingly, SR 57227A specifically reduced subsequent current amplitudes induced by 5-HT or SR 57227A. Based on its 5-HT3 receptor partial agonist/partial antagonist properties, we predict that SR 57227A functions as a serotonin stabilizer.

Effects of preoperative cisapride on postoperative aspiration pneumonia in dogs with laryngeal paralysis.

Retrospective evaluation of a preoperative prokinetic protocol using a constant-rate infusion of a serotonin 5-HT4 receptor agonist, cisapride, and its association with frequency of postoperative aspiration pneumonia in dogs undergoing unilateral arytenoid lateralisation as compared to a historical population at the same institution. Medical records of dogs undergoing unilateral arytenoid lateralisation for laryngeal paralysis were reviewed for historical findings, imaging findings, anaesthesia and surgery durations, perioperative medications and if surgery was performed as an emergency. Aspiration pneumonia events in the first 72 hours after surgery were recorded. The study group received a preoperative cisapride constant-rate infusion; historical 'controls' did not receive the cisapride protocol. One of 50 dogs in the cisapride group and six of 52 dogs in the historical group developed aspiration pneumonia within the immediate postoperative period. The cisapride protocol was largely well tolerated. A markedly lower rate of aspiration pneumonia in patients administered butorphanol with acepromazine preoperatively and buprenorphine postoperatively was noted, but the overall low frequency of aspiration pneumonia and variation in case management protocols precluded definitive conclusions with respect to optimal perioperative drug choices. Laryngeal paralysis is commonly treated by unilateral arytenoid lateralisation, and aspiration pneumonia is one of the most serious potential complications of this procedure. This study suggests that further investigation of a cisapride constant-rate infusion to prevent this complication is warranted.

Efficacy and Safety of Serotonin Receptor Ligands in the Treatment of Irritable Bowel Syndrome: A Review.

Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished. This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients. We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.

5-HT3 receptor signaling in serotonin transporter-knockout rats: a female sex-specific animal model of visceral hypersensitivity

The irritable bowel syndrome (IBS) is a functional gastrointestinal motor and visceral sensation disorder that is more common in women than men. Female serotonin transporter (SERT)-gene knockout (KO) rats exhibit hypersensitivity to colorectal balloon distention (CRD) that mimics colonic hypersensitivity occurring in female IBS patients. Alosetron (5-HT3 receptor antagonist) is used to treat diarrhea-predominant IBS in female patients. Other 5-HT3 receptor antagonists are ineffective at treating IBS symptoms. The visceromotor response (VMR) to CRD in SERT-KO and wild-type (WT) rats was measured following subcutaneous (sc), intracerobroventricular (icv), or intrathecal (it) treatment with 5-HT3 receptor antagonists and an agonist. Alosetron (sc) and granisetron (antagonists) caused a paradoxical increase in the VMR to CRD in SERT-KO female rats. Alosetron (sc) increased the VMR to CRD in WT male rats. Alosetron (it) increased the VMR to CRD in SERT-KO female rats only, and the 5-HT3 receptor agonist SR-52772 increased the VMR to CRD in SERT-KO male rats. Depletion of spinal 5-HT using 5,7-dihydroxytryptamine prevented the increase in VMR to CRD in SERT-KO female and male rats treated it with alosetron and SR-52772, respectively. Alosetron (icv) did not affect the VMR to CRD in WT or KO female rats, but it increased the VMR in male SERT-KO but not WT male rats. These data suggest that 5-HT3 receptor signaling at the dorsal spinal cord mediates visceral hypersensitivity in female SERT-KO rats. Such differences could facilitate development of sex-specific drug treatments for visceral pain. NEW & NOTEWORTHY We studied a model of female sex-specific visceral hypersensitivity using rats that had a loss of function of the serotonin transporter (SERT) caused by gene truncation. Female SERT-KO rats exhibited visceral hypersensitivity in response to colorectal balloon distention. We found that increased 5-HT signaling at dorsal spine 5-HT3 receptors was responsible for visceral hypersensitivity in female but not male SERT-KO rats.

Classification (Agonist/Antagonist) and Regression "Structure-Activity" Models of Drug Interaction with 5-HT6.

One promising target for novel psychotropic drugs is the 5-HT6 receptor, GProtein- Coupled Receptor (GPCR) family, displaying seven transmembrane domains. There is considerable interest in how both 5-HT6 receptor agonist and antagonist compounds can have marked procognitive effects. An exact structure of the 5-HT6 receptor is not available, so application of powerful methods of (Q)SAR and molecular modelling, which play an essential role in modern drug design, are currently limited to structure-based homology models. The present study is devoted to a detailed QSAR analysis of 61 drugs (26 agonists and 35 antagonists) acting on the 5-HT6 receptor (rattus norvegicus and homo sapiens). Five classification methods were used: k-Nearest Neighbors (k-NN), Logistic Regression (LG), Linear Discriminant Analysis (LDA), Random Forest (RF), and Support Vector Machine (SVM). Multiple Regression Analysis (MRA) was involved also for regression analysis. Spectra of Inter Atomic Interactions (SIAI) were applied in the search for ligand centres interacting with the 5- HT6 receptor. SAR and QSAR models based on the use of HYBOT, MOLTRA, VolSurf+, and SYBYL programs, and having cross-validated coefficients of determination of at least 0.80, show a predominant influence of H-bond acceptor ability and hydrophobicity on the type of ligand activity and degree of inhibition.

Sumatriptan inhibits the electrophysiological activity of ASICs in rat trigeminal ganglion neurons

Sumatriptan, a selective serotonin 5-HT1 receptor agonist, is an effective therapeutic for migraine attacks. However, the molecular mechanisms underlying sumatriptan migraine relief are still not fully understood. Here, we found that acid-sensing ion channels (ASICs), pH sensors, are peripheral targets of sumatriptan against migraine. Sumatriptan can inhibit the electrophysiological activity of ASICs in the trigeminal ganglion (TG) neurons. In the present study, sumatriptan decreased proton-gated currents mediated by ASICs in a concentration-dependent manner. In addition, sumatriptan shifted concentration-response curves for protons downwards, with a decrease of 37.3 ± 4.6% in the maximum current response but with no significant change in the pH0.5 value. Sumatriptan inhibition of ASIC currents was blocked by 5-HT1D receptor antagonist BRL 15572, but not by 5-HT1B antagonist SB 224289. Moreover, the sumatriptan inhibition of ASICs can be mimicked by the 5-HT1D receptor agonist L-694,247, but not by the 5-HT1B agonist CP-93129. Sumatriptan inhibition of ASIC currents was also reversed by G-protein αi subunit inhibitor PTX and 8-Br-cAMP, suggesting the inhibition may involve the intracellular signal transduction. Finally, sumatriptan decreased the number of action potentials induced by acid stimuli in rat TG neurons. Our results indicated that the anti-migraine drug, sumatriptan, inhibited ASICs in rat TG neurons via 5-HT1D receptor subtype and a cAMP-dependent signal pathway. These observations add to the understanding of the mechanisms that underlie the clinical effectiveness of anti-migraine sumatriptan.

Co-activation of both 5-HT1A and 5-HT7 receptors induced attenuation of glutamatergic synaptic transmission in the rat visual cortex

It has been suggested that functional interactions between the 5-HT receptor subtypes may modulate glutamatergic synaptic transmission. In this study, we used whole-cell patch-clamp recordings to test the role of 5-HT receptors in mediating the AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the AMPA receptor-mediated component of mEPSCs could be inhibited by exogenously applied 5-HT. 5-HT significantly reduced the glutamatergic mEPSC amplitude and increased the inter-event interval of glutamatergic mEPSCs. Bath application of 5-CT or 8-OH-DPAT (the 5-HT1A and 5-HT7 receptor agonist) mimicked 5-HT in its effect on mEPSCs. Additionally, a selective antagonist for the 5-HT7 receptor, SB-269970, displayed no influence on the inhibition of glutamatergic synaptic transmission by 5-CT or 8-OH-DPAT. Similar results were obtained by exogenously applied WAY-100135, the selective 5-HT1A receptor antagonist. However, the inhibition of glutamatergic synaptic transmission by 5-CT or 8-OH-DPAT was completely blocked by co-application of WAY-100135 and SB-269970. Altogether, our results indicated that 5-HT suppressed glutamatergic synaptic transmission by co-activation of synaptic 5-HT1A receptors and 5-HT7 receptors in layer II/III pyramidal neurons of the rat visual cortex.

Prucalopride for the treatment of delayed gastric emptying after pancreaticoduodenectomy: a pilot study

Introduction: Delayed gastric emptying (DGE) is one of the most common complications after pancreaticoduodenectomy (PD) reported in 19–57% of patients. Prucalopride, a 5-hydroxytryptamine, 5HT-4 receptor agonist has been shown to be an excellent drug to treat post-operative ileus. In this pilot study we wanted to test Prucalopride in the treatment of DEG after PD. Methods: We conducted a monocentric study on a consecutive series of PD performed in patients affected by pancreatic adenocarcinomas from January 2013 to December 2017 at IRCCS-ISMETT-UPMC. Patient's demographics, oncologic staging, operative times, intraoperative vitals, and all early surgey-related complications using Clavien grading system were collected and analyzed. Post-operative DGE was determined by the inability to return to a standard diet by the end of the first post-operative week and includes prolonged nasogastric intubation on the patient. Results: There were 96 consecutive patients who underwent PD in our department between January 2013 and December 2017. Multivariate analyses were performed to investigate the effectiveness of the Prucalopride in the treatment of DGE. The overall incidence of DGE was 26,04 % (patients underwent PD: 96, patient with DGE post PD: 25) Of these, 7 patients (6 F, 1 M) were treated with Prucalopride after the failure of medical therapy with common prokinetic (metoclopramide, domperidone). Each of these had a resolution of the DGE with improvement of the outcome and with early discharge. Conclusion: Prucalopride may serve as a post-operative tool for DGE after PD, further studies are needed to validate this proof of concept.