The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Michael Camilleri - One of the best experts on this subject based on the ideXlab platform.
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Emerging pharmacologic therapies for irritable bowel syndrome.
Current Gastroenterology Reports, 2010Co-Authors: Noriaki Manabe, Banny S. Wong, Michael CamilleriAbstract:New therapies are being developed for irritable bowel syndrome (IBS). These advances are based on understanding pathophysiology or the development of medications with greater selectivity in classes of agents with known efficacy. Prucalopride, the newest European Medicines Agency-approved 5-hydroxytryptamine receptor 4 (5-HT4) Agonist, is effective in the treatment of chronic constipation with improved cardiovascular safety relative to older 5-HT4 drugs; similarly, ramosetron, the 5-hydroxytryptamine receptor 3 (5-HT3) antAgonist, appears efficacious in diarrhea-predominant IBS. Secretagogues with different mechanisms of action target apical domains in enterocytes that are involved in chloride secretion, such as chloride channels, the cystic fibrosis transmembrane regulator, and guanylate cyclase C. As a class, such secretagogues have high efficacy and safety for constipation. With more data obtained from phase 2 and 3 trials, we expect other classes of medications, including bile acid modulators, anti-inflammatory agents, visceral analgesics, and newer centrally acting agents to be efficacious and enter the armamentarium for the treatment of IBS in the future.
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Role of prucalopride, a serotonin (5-HT4) receptor Agonist, for the treatment of chronic constipation
Clinical and Experimental Gastroenterology, 2010Co-Authors: Banny S. Wong, Noriaki Manabe, Michael CamilleriAbstract:Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden. Many patients with chronic constipation are dissatisfied with current therapy due to lack of long-term efficacy or side effects. Previous nonselective 5-hydroxytryptamine receptor 4 (5-HT4) Agonists have been associated with significant interactions with other receptors (5-HT1B, 5-HT1D, and 5-HT2B for tegaserod; hERG for cisapride), leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market. Prucalopride is a novel gastrointestinal prokinetic agent. It acts as a high affinity, highly-selective 5-HT4 Agonist. Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit, bowel function, gastrointestinal symptoms, and quality of life, with benefit maintained for up to 24 months in open label, multicenter, follow-up studies. Prucalopride’s high selectivity for the 5-HT4 receptor may explain its favorable safety and tolerability profiles, even in elderly subjects with stable cardiovascular disease. Prucalopride is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first-line treatments.
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Stomach Dysfunction in Diabetes Mellitus: Emerging Technology and Pharmacology
Journal of diabetes science and technology, 2010Co-Authors: Lawrence A. Szarka, Michael CamilleriAbstract:Gastroparesis and other types of gastric dysfunction result in substantial morbidity in diabetes patients. The pathophysiology of these disorders is incompletely understood. This article reviews techniques applicable to the assessment of gastric function in diabetes patients, including the measurement of emptying, accommodation, and contractility. Available treatment options are also reviewed, including novel yet unapproved serotonin 5-HT4 Agonist pharmacological treatments, as well as the role of endoscopic, surgical, and device treatments of gastroparesis.
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Genetics and Irritable Bowel Syndrome: From Genomics to Intermediate Phenotype and Pharmacogenetics
Digestive Diseases and Sciences, 2009Co-Authors: Michael CamilleriAbstract:Purpose Familial aggregation and sibling pair studies suggest there is a genetic contribution to the development of irritable bowel syndrome (IBS). The aim of this study was to review the evidence of genetics in IBS based on genetic epidemiology, studies of association with intermediate phenotypes and pharmacogenetics. Results Genetic association studies with IBS symptom phenotype have generally provided inconsistent results for many candidate genes investigated, such as SLC6A4 , GNB3 , and IL-10 . There have been no genome-wide association studies in IBS to date. Studies of associations of candidate genes with intermediate phenotypes suggest associations with pathophysiological mechanisms of motor and sensory functions; however, these results also require replication. Pharmacogenetics studies illustrate the potential of genetics to impact on response to therapy, as observed with SLC6A4 and responses to the 5-HT3 antAgonist alosetron and the 5-HT4 Agonist, tegaserod. Conclusions While the heritable component and genetics in the complex disorder of IBS are still poorly understood, studies of the associations of spontaneous genetic variations and altered functions may provide novel insights of the mechanisms contributing to the disease.
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Does co-administration of a non-selective opiate antAgonist enhance acceleration of transit by a 5-HT4 Agonist in constipation-predominant irritable bowel syndrome? A randomized controlled trial.
Neurogastroenterology and Motility, 2007Co-Authors: Amy E. Foxx-orenstein, Michael Camilleri, Lawrence A. Szarka, S. Mckinzie, D. Burton, G. Thomforde, K. Baxter, Alan R. ZinsmeisterAbstract:Abstract Opioid neurons exhibit tonic restraint on intestinal motility; opioid antAgonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) Agonists combined with selective opioid antAgonists significantly increased colonic propulsion relative to a 5-HT4 Agonist alone. We hypothesized that the combination of 5-HT4 Agonist and non-selective opioid antAgonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P
Jan Tack - One of the best experts on this subject based on the ideXlab platform.
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Tegaserod: a new 5-HT4 Agonist in the treatment of irritable bowel syndrome
Expert Opinion on Pharmacotherapy, 2020Co-Authors: Jan Tack, Maura CorsettiAbstract:Tegaserod is a selective partial Agonist acting on serotonergic type 4 receptors (5-HT4). Pharmacodynamic studies indicate that tegaserod is able to stimulate gut propulsion and secretion with a net prokinetic effect. In contrast to other 5-HT4 Agonists endowed with a complex pharmacological profile, tegaserod has a reliable prokinetic activity in the colon. Clinical trials show that tegaserod is effective and safe in the treatment of patients with irritable bowel syndrome. In particular, tegaserod relieves symptoms of abdominal pain, discomfort, abdominal bloating and constipation.
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Randomised clinical trial: the 5-HT4 Agonist revexepride in patients with gastro-oesophageal reflux disease who have persistent symptoms despite PPI therapy.
Alimentary Pharmacology & Therapeutics, 2015Co-Authors: Nicholas J. Shaheen, Jan Tack, Philip B. Miner, J Adler, S. Dedrie, D. A. Johnson, Peter Malfertheiner, A. Meulemans, L Poole, L. ThielemansAbstract:Summary Background A substantial proportion of patients with gastro-oesophageal reflux disease (GERD) have only a partial response to proton pump inhibitor (PPI) therapy. Prokinetic drugs may improve reflux symptoms by enhancing oesophageal motility and gastric emptying. Aim To evaluate the effect of revexepride, a novel prokinetic 5-hydroxytryptamine type 4 (5-HT4) receptor Agonist, compared with placebo, in patients with GERD who have a partial response to PPIs. Methods A phase 2b, double-blind, parallel-group study was conducted, in which patients were randomised to one of three revexepride treatment groups (0.1, 0.5 and 2.0 mg three times daily) or placebo (1:1:1:1 ratio). Daily e-diary data captured patients' symptoms over an 8-week treatment period. The primary efficacy outcome was the weekly percentage of regurgitation-free days in the second half of the study (weeks 5–8). Results In total, 480 patients were randomised and 477 received treatment (mean age 47.9 years; 61% women). The mean percentage of regurgitation-free days increased from baseline (range, 15.0–18.8%) to week 8 (62.3–70.5%) in all four study arms; however, there were no statistically significant differences in this change between placebo and the three treatment arms. No dose-dependent relationship in treatment effect was observed for any of the study endpoints. The incidence of treatment-emergent adverse events (TEAEs) was revexepride dose-dependent. Only one serious TEAE occurred and none resulted in death. Conclusions Revexepride was no more effective than placebo in controlling regurgitation in patients with GERD symptoms partially responsive to PPIs. Revexepride was well tolerated. ClinicalTrials.gov Identifier: NCT01472939.
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Current and future therapies for chronic constipation
Best Practice & Research in Clinical Gastroenterology, 2011Co-Authors: Jan TackAbstract:In this article, traditional and novel therapies for chronic constipation are reviewed. Traditional laxatives are effective at inducing bowel movements, but efficacy in long-term management and efficacy on constipation-associated abdominal symptoms are less well established, with the exception of polyethylene glycol, for which long-term studies confirm sustained efficacy. Recently approved drugs include the colonic secretagogue lubiprostone and the 5-HT4 Agonist prucalopride. In controlled trials in chronic constipation, these drugs were shown to significantly improve constipation and its associated symptoms, with a favourable safety record. Methylnaltrexone, a subcutaneously administered peripherally acting mu opioid receptor antAgonist, has recently been approved for opioid-induced constipation in terminally ill patients. New agents under evaluation include the 5-HT4 Agonists velusetrag and naronapride, the guanylate cyclase-C receptor Agonist linaclotide and the peripherally acting mu opioid receptor antAgonist alvimopan.
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Renzapride: a new drug for the treatment of constipation in the irritable bowel syndrome
Expert Opinion on Investigational Drugs, 2008Co-Authors: Emidio Scarpellini, Jan TackAbstract:Renzapride is a novel drug currently under clinical evaluation for the treatment of irritable bowel syndrome (IBS). Renzapride is a mixed 5-hydroxytryptamine type 4 (5-HT4) Agonist and 5-HT3 receptor antAgonist that has a stimulatory effect on gastrointestinal motility and transit, as established by in vivo and in vitro studies. Its therapeutic efficacy, tolerability and safety have been evaluated in diabetic gastroparesis in a single study, as well as in IBS in a few other studies. Phase II studies indicated potential beneficial effects on symptoms and bowel habits in patients with constipation-predominant IBS and mixed-type IBS. The outcome of Phase III studies is currently under evaluation.
Bernard Soumireu-mourat - One of the best experts on this subject based on the ideXlab platform.
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Differential modulation of the 5-HT4 receptor Agonists and antAgonist on rat learning and memory
Neuropharmacology, 2000Co-Authors: Evelyne Marchetti, Aline Dumuis, Bernard Soumireu-mourat, Joel Bockaert, Francois RomanAbstract:Abstract Recent data suggest that activation of 5-HT4 receptors may modulate cognitive processes such as learning and memory. In the present study, the effects of two potent and selective 5-HT4 Agonists, RS 17017 [1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)-1-pentanone hydrochloride] and RS 67333 [1(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone], were studied in an olfactory associative discrimination task. The implication of 5-HT4 receptors in the associative discriminative task was suggested by the following observation. Injection of a selective 5-HT4 receptor antAgonist RS 67532 [1-(4-amino-5-chloro-2-(3,5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg: i.p.] before the third training session induced a consistent deficit in associative memory during the following training sessions. This deficit was absent when the antAgonist was injected together with either a specific hydrophilic 5-HT4 (RS 17017, 1 mg/kg) or a specific hydrophobic (RS 67333, 1 mg/kg) 5-HT4 receptor Agonist. RS 67333 was more potent than RS 17017. This difference in potency certainly reflects a difference in their capacity to enter into the brain. This is also likely to be the reason why, injected alone, the hydrophobic 5-HT4 Agonist (RS 67333) but not the hydrophilic 5-HT4 Agonist (RS 17017) improved learning and memory performance.
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BIMU1 increases associative memory in rats by activating 5-HT4 receptors.
Neuropharmacology, 1997Co-Authors: E Marchetti-gauthier, Aline Dumuis, Joel Bockaert, F S Roman, Bernard Soumireu-mouratAbstract:Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo -1 H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 Agonist/5-HT3 antAgonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluro-2-methoxy-1H-indole-3- carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antAgonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (> 15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory.
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BIMU1 Increases Associative Memory in Rats by Activating 5-HT4 Receptors
Neuropharmacology, 1997Co-Authors: E Marchetti-gauthier, Aline Dumuis, Francois Roman, Joel Bockaert, Bernard Soumireu-mouratAbstract:Abstract Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo-1H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 Agonist/5-HT3 antAgonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antAgonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (>15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory. © 1997 Elsevier Science Ltd.
Joel Bockaert - One of the best experts on this subject based on the ideXlab platform.
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VRX-03011, a novel 5-HT4 Agonist, enhances memory and hippocampal acetylcholine efflux.
Neuropharmacology, 2007Co-Authors: Eric G. Mohler, Aline Dumuis, Sharon Shacham, Silvia Noiman, Frank Lezoualc'h, Sylvain J. Robert, Monique Gastineau, Joseph Rutkowski, Yael Marantz, Joel BockaertAbstract:Abstract Recent evidence suggests that 5-hydroxytryptamine (5-HT)4 receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT4 Agonist, that is both potent (Ki ∼ 30 nM) and highly selective (Ki > 5 μM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1–10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non-amyloidogenic soluble form of APP (sAPPα) with an EC50 ∼ 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC50 > 10 μM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects.
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Differential modulation of the 5-HT4 receptor Agonists and antAgonist on rat learning and memory
Neuropharmacology, 2000Co-Authors: Evelyne Marchetti, Aline Dumuis, Bernard Soumireu-mourat, Joel Bockaert, Francois RomanAbstract:Abstract Recent data suggest that activation of 5-HT4 receptors may modulate cognitive processes such as learning and memory. In the present study, the effects of two potent and selective 5-HT4 Agonists, RS 17017 [1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)-1-pentanone hydrochloride] and RS 67333 [1(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone], were studied in an olfactory associative discrimination task. The implication of 5-HT4 receptors in the associative discriminative task was suggested by the following observation. Injection of a selective 5-HT4 receptor antAgonist RS 67532 [1-(4-amino-5-chloro-2-(3,5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg: i.p.] before the third training session induced a consistent deficit in associative memory during the following training sessions. This deficit was absent when the antAgonist was injected together with either a specific hydrophilic 5-HT4 (RS 17017, 1 mg/kg) or a specific hydrophobic (RS 67333, 1 mg/kg) 5-HT4 receptor Agonist. RS 67333 was more potent than RS 17017. This difference in potency certainly reflects a difference in their capacity to enter into the brain. This is also likely to be the reason why, injected alone, the hydrophobic 5-HT4 Agonist (RS 67333) but not the hydrophilic 5-HT4 Agonist (RS 17017) improved learning and memory performance.
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BIMU1 increases associative memory in rats by activating 5-HT4 receptors.
Neuropharmacology, 1997Co-Authors: E Marchetti-gauthier, Aline Dumuis, Joel Bockaert, F S Roman, Bernard Soumireu-mouratAbstract:Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo -1 H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 Agonist/5-HT3 antAgonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluro-2-methoxy-1H-indole-3- carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antAgonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (> 15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory.
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BIMU1 Increases Associative Memory in Rats by Activating 5-HT4 Receptors
Neuropharmacology, 1997Co-Authors: E Marchetti-gauthier, Aline Dumuis, Francois Roman, Joel Bockaert, Bernard Soumireu-mouratAbstract:Abstract Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo-1H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 Agonist/5-HT3 antAgonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antAgonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (>15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory. © 1997 Elsevier Science Ltd.
Aline Dumuis - One of the best experts on this subject based on the ideXlab platform.
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VRX-03011, a novel 5-HT4 Agonist, enhances memory and hippocampal acetylcholine efflux.
Neuropharmacology, 2007Co-Authors: Eric G. Mohler, Aline Dumuis, Sharon Shacham, Silvia Noiman, Frank Lezoualc'h, Sylvain J. Robert, Monique Gastineau, Joseph Rutkowski, Yael Marantz, Joel BockaertAbstract:Abstract Recent evidence suggests that 5-hydroxytryptamine (5-HT)4 receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT4 Agonist, that is both potent (Ki ∼ 30 nM) and highly selective (Ki > 5 μM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1–10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non-amyloidogenic soluble form of APP (sAPPα) with an EC50 ∼ 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC50 > 10 μM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects.
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Differential modulation of the 5-HT4 receptor Agonists and antAgonist on rat learning and memory
Neuropharmacology, 2000Co-Authors: Evelyne Marchetti, Aline Dumuis, Bernard Soumireu-mourat, Joel Bockaert, Francois RomanAbstract:Abstract Recent data suggest that activation of 5-HT4 receptors may modulate cognitive processes such as learning and memory. In the present study, the effects of two potent and selective 5-HT4 Agonists, RS 17017 [1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)-1-pentanone hydrochloride] and RS 67333 [1(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone], were studied in an olfactory associative discrimination task. The implication of 5-HT4 receptors in the associative discriminative task was suggested by the following observation. Injection of a selective 5-HT4 receptor antAgonist RS 67532 [1-(4-amino-5-chloro-2-(3,5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg: i.p.] before the third training session induced a consistent deficit in associative memory during the following training sessions. This deficit was absent when the antAgonist was injected together with either a specific hydrophilic 5-HT4 (RS 17017, 1 mg/kg) or a specific hydrophobic (RS 67333, 1 mg/kg) 5-HT4 receptor Agonist. RS 67333 was more potent than RS 17017. This difference in potency certainly reflects a difference in their capacity to enter into the brain. This is also likely to be the reason why, injected alone, the hydrophobic 5-HT4 Agonist (RS 67333) but not the hydrophilic 5-HT4 Agonist (RS 17017) improved learning and memory performance.
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BIMU1 increases associative memory in rats by activating 5-HT4 receptors.
Neuropharmacology, 1997Co-Authors: E Marchetti-gauthier, Aline Dumuis, Joel Bockaert, F S Roman, Bernard Soumireu-mouratAbstract:Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo -1 H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 Agonist/5-HT3 antAgonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluro-2-methoxy-1H-indole-3- carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antAgonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (> 15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory.
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BIMU1 Increases Associative Memory in Rats by Activating 5-HT4 Receptors
Neuropharmacology, 1997Co-Authors: E Marchetti-gauthier, Aline Dumuis, Francois Roman, Joel Bockaert, Bernard Soumireu-mouratAbstract:Abstract Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo-1H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 Agonist/5-HT3 antAgonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antAgonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (>15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory. © 1997 Elsevier Science Ltd.
