Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists

Wolf, Helmut

doi:10.1080/030097400446625

Cited by 99 publications

(67 citation statements)

References 41 publications

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“…Indeed, others have shown that tropisetron passes the blood-brain barrier and exerts multiple effects in the central nervous system, possibly also weight control effects. 31 On the other hand, central effects of tropisetron with regard to weight change, appetite control or obesity have not been reported. Our data, together with previous publications, suggest that a suppression of the serotonergic system in the intestine may result in alterations of food intake and weight regulation.…”

Section: Discussionmentioning

confidence: 99%

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

et al. 2009

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Objective: Sugar consumption has increased markedly over the last few decades and parallels the dramatic increase in overweight and obesity. Data obtained from animal studies suggest that the intestinal serotonergic system and herein particularly the serotonin receptor 3 (5-HT3R) may be involved in sugar detection and short-term control of food intake. Using a mouse model, we tested the hypothesis that blocking 5-HT3R prevents the development of sugar-induced obesity. Design: For 8 weeks, C57BL/J6 mice were offered either water containing 30% glucose or plain water in addition to normal chow. The effect of oral treatment with the 5-HT3R antagonist, tropisetron (0.2 mg kg À1 body weight), on body weight and caloric intake was studied. Results: Total caloric intake and weight gain were significantly increased in mice fed glucose compared with the control group. Tropisetron treatment reduced intestinal motility and almost completely blocked weight gain associated with glucose feeding; however, total caloric intake was not affected. The effect of tropisetron was not associated with a decreased expression of the intestinal and hepatic glucose transporters, SGLT1 (sodium-dependent glucose cotransporter) and Glut2 (glucose transporter 2); instead, the expression of these transporters was slightly increased by the 5-HT3R antagonist. However, expressions of carbohydrate responsive element binding protein and fatty acid synthase, as well as triglyceride levels in the liver were only enhanced in mice fed glucose, but remained unchanged at the level of the control group when mice were treated concomitantly with tropisetron. At the same time, b-hydroxybutyrate dehydrogenase mRNA expression and plasma levels of ketone bodies were significantly increased. Conclusion: Our results suggest that 5-HT3R is a new target for the modulation of hepatic glucose metabolism and for the prevention of obesity.

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Section: Discussionmentioning

confidence: 99%

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

et al. 2009

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“…15 Ondansetron is a specific 5-HT3 receptor antagonist with negligible agonistic or antagonistic activity at alpha or beta-adrenergic and histamine, muscarinic, central or peripheral dopaminergic receptors. 14,15 Our results show that the oral administration of 8 mg of ondansetron two hours before the studies did not significantly improve the breathholding time or the degree of respiratory discomfort induced by different inspiratory loads in a group of 10 healthy young volunteers, but it led to small changes in respiratory physiological parameters (Figures 1 and 2 and Table 1). Decreases in tidal volume associated with drug intake were observed at all respiratory loads, although they reached statistical significance only under basal conditions and when breathing under a load of 21 cm H 2 O/l/sec.…”

Section: Discussionmentioning

confidence: 83%

“…Although the current clinical use of ondansetron is exclusively as an anti-emesis agent, a great number of additional uses for the drug have been described. [9][10][11][12][13][14] Moreover, there is evidence to support a role for 5-HT receptors in neural respiratory control. 7 Serotonin may be particularly important in metabolic states such as hypoxia or ischemia that cause apneustic breathing, since 5-HT restores normal breathing pattern under these conditions.…”

Section: Discussionmentioning

confidence: 99%

“…9 In addition, new uses for ondansetron have been described, including the reduction of drinking among subjects predisposed to alcoholism, anxiolysis, attenuation of age-associated memory impairment, anti-psychotic effects in Parkinson's disease, and improvements in migraine and nervous bulimia patients. [10][11][12][13][14] Ondansetron also promotes reduction of digestive secretions and diarrhea caused by increased intestinal serotonin content and a decrease in experimentally induced pain. 14,15 Even though a substantial number of pharmacological actions have been demonstrated for ondansetron, no study has yet been published dealing with its potential effects on breathlessness.…”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12][13][14] Ondansetron also promotes reduction of digestive secretions and diarrhea caused by increased intestinal serotonin content and a decrease in experimentally induced pain. 14,15 Even though a substantial number of pharmacological actions have been demonstrated for ondansetron, no study has yet been published dealing with its potential effects on breathlessness.…”

Section: Introductionmentioning

confidence: 99%

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Effects of ondansetron on respiratory pattern and sensation of experimentally induced dyspnea

et al. 2002

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CONTEXT: Dyspnea remains a therapeutic challenge, especially in chronic respiratory conditions. Recent studies have shown that the induction of unpleasant dyspnea sensations activates areas in the insular cortex. OBJECTIVE: This study was designed to investigate the potential effects of ondansetron, a potent anti-serotonin agent, on induced dyspnea sensation. TYPE OF STUDY: A randomized double blind study. SETTING: Pulmonary Function Laboratory of Hospital das Clínicas de Ribeirão Preto. PARTICIPANTS: Ten healthy male volunteers (mean age ± standard error = 23.1 ± 0.41 years) without respiratory diseases and showing normal spirometric tests. INTERVENTIONS: Uncomfortable breathing was induced in the volunteers on two different days, via the use of inspiratory resistors (loads of 0, 7, 14 and 21 cm H2O/l/sec) and breathholding, two hours after taking 8 mg of ondansetron (Ond) or placebo (Plac). MAIN MEASUREMENTS: Respiratory discomfort during breathing under loading was evaluated on a 100-mm visual analog scale. The maximum length of time of voluntary apnea was measured in seconds. RESULTS: The mean maximum voluntary apnea time did not differ between the ondansetron and placebo days (Plac = 96 ± 6.6 sec vs. Ond = 100 ± 7.9 sec). Ondansetron did not influence the dyspnea sensation induced by different inspiratory loads (0 cm H2O/l/sec: Ond = 1.4 mm ± 0.44 vs. Plac = 2.1 ± 0.85 mm; 7 cm H2O/l/sec: Ond = 16.6 ± 2.74 mm vs. Plac = 13.7 ± 2.06 mm; 14 cm H2O/l/sec; Ond = 30.5 ± 4.50 mm vs. Plac = 27.1 ± 3.44 mm; 21 cm H2O/l/sec: Ond = 50.3 ± 6.72 mm vs. Plac = 49.4 ± 6.72 mm). Ondansetron led to significant decreases in tidal volume under basal conditions and when breathing under the highest inspiratory loading (0 cm H2O/l/sec: Ond = 0.83 ± 0.26 l vs. Plac = 1.0 ± 0.28 l; 21 cm H2O/l/sec: Ond = 0.86 ± 0.23 l vs. Plac = 1.1 ± 0.22 l) CONCLUSION: The present results suggest that 5-HT3 receptors do not play an important role in the mediation of dyspnea sensations.

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Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT₃ Receptor Antagonists with Antidepressant‐Like Activity

Dhar

Mahesh

Jindal

et al. 2015

Archiv der Pharmazie

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Series of piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides were designed using a ligand-based approach with consideration of the pharmacophoric requirements for 5-HT3 receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5-HT3 receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5-HT3 agonist, 2-methyl-5-hydroxytryptamine, which was denoted in the form of pA2 values. The structure-activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5-HT3 pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h exhibited prominent 5-HT3 receptor antagonism with pA2 values of 7.5 and 7.3, respectively. Subsequent investigation of the antidepressant activities of selected compounds in the mouse forced swim test (FST) led to the identification of the piperazine analogs of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h as the most promising compounds. Both 13i and 8h demonstrated significant reduction in the duration of immobility as compared to the control. Importantly, none of the tested compounds affected the baseline locomotion of mice at the tested dose levels.

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Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists

Cited by 99 publications

References 41 publications

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

Effects of ondansetron on respiratory pattern and sensation of experimentally induced dyspnea

Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT₃ Receptor Antagonists with Antidepressant‐Like Activity

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Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists

Cited by 99 publications

References 41 publications

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

Effects of ondansetron on respiratory pattern and sensation of experimentally induced dyspnea

Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT3 Receptor Antagonists with Antidepressant‐Like Activity

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Product

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Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT₃ Receptor Antagonists with Antidepressant‐Like Activity