Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA(C) receptors belong to the nicotinicoid superfamily of ionotropic receptors that include nicotinic acetylcholine receptors, bicuculline-sensitive GABA(A) receptors, strychnine-sensitive glycine receptors and 5HT3 serotonin receptors. The GABA(C) receptor concept arose from medicinal chemical studies of a conformationally restricted analog of GABA. Receptors matching the predicted properties of GABA(C) receptors were cloned from the retina. Post cloning studies revealed the unique physiology and pharmacology of these relatively simple homomeric receptors. Three subtypes of GABA(C) receptors have been cloned from mammalian sources and pharmacological differences between the rho1, rho2 and rho3 GABA(C) receptors have been described. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and the gut and their involvement in vision, aspects of memory and sleep-waking behaviour. This review concentrates on the medicinal chemistry and molecular pharmacology of GABA(C) receptor subtypes emphasising possible new investigational tools with which to investigate further GABA(C) receptor function. The most useful currently available ligands that show some GABA(C) receptor subtype selectivity are TPMPA, P4PMA, imidazole-4-acetic acid, 2-methyl-TACA and (+/-)-TAMP.
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PMID:Medicinal chemistry and molecular pharmacology of GABA(C) receptors. 1217 79

Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visccral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin. A, N-methyl-D-aspartate, alpha 2-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.
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PMID:Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds. 1218 41

Although the enteric reflex pathway triggered by volume distension is known to depend on an adrenergic nerve, it is not known whether the slowing of intestinal transit by fat or peptide YY (PYY) also depends on an adrenergic pathway. The aim of this study was to test the hypotheses that the slowing of transit by fat or PYY may depend on a beta-adrenergic pathway, and this adrenergic pathway may act via the serotonergic and opioid pathways previously observed for the slowing of transit by fat. Eighteen dogs were equipped with duodenal and midgut fistulas. The small intestine was compartmentalized into the proximal and distal half of gut. The role of adrenergic, serotonergic, and opioid pathways was then tested in the slowing of intestinal transit by fat, PYY, and norepinephrine. Intestinal transit results were compared as the cumulative percent marker of recovery over 30 min. We found that the slowing of transit by fat, PYY, or norepinephrine was reversed by propranolol. In addition, the slowing effect of fat was reversed by metoprolol (beta1-adrenoreceptor antagonist) but not phentolamine (alpha-adrenoreceptor antagonist). Furthermore, norepinephrine-induced slowing of transit was reversed by ondansetron (5-HT3 receptor antagonist) or naloxone (opioid receptor antagonist). Extending these physiological results, we also found by immunohistochemistry that beta1-adrenoreceptors are expressed by neurons of the intrinsic plexuses of the small intestine. We conclude that the slowing of intestinal transit by fat or PYY depends on a beta-adrenergic pathway and that this adrenergic pathway acts on serotonergic and opioid pathways.
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PMID:Slowing of intestinal transit by fat or peptide YY depends on beta-adrenergic pathway. 1461 22

Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal (GI) disorder, affecting about 20% of the world's population. Chronic abdominal pain or discomfort relieved by defecation and associated with altered bowel habits are the mainstay in diagnosis. The pathophysiology of IBS remains unknown. This biopsychosocial disorder involves dysregulation of the nervous system, altered intestinal motility, and increased visceral sensitivity. All of these result from dysregulation of the bidirectional communication between the gut with its enteric nervous system and the brain (the brain-gut axis), modulated by various psychosocial and environmental factors (e.g. infection, inflammation). Numerous neurotransmitters are found in the brain and gut that regulate GI activities, including 5-hydroxytryptamine (5-HT, serotonin) and its 5-HT3 and 5-HT4 receptors. The current approach to IBS patients is based on a positive diagnosis of the symptom complex, exclusion of underlying organic disease, and institution of a therapeutic trial. Traditional symptomatic treatment has included antidiarrheals, laxatives and bulking agents/fiber, low-dose tricyclic antidepressants, antispasmodics for pain, and "alternative" therapies (e.g. psychotherapy, hypnotherapy). The scientific evidence supporting this therapy is limited. Novel approaches include visceral analgesics and serotonin agonists and antagonists. In patients with severe diarrhea, 5-HT3 receptor antagonists (e.g. alosetron) and selective M3-type anticholinergics are indicated, in constipation 5-HT4 agonists (e.g. tegaserod), and in pain alfa2-adrenergics (e.g. clonidine), cholecystokinin antagonists, kappa-opioid agonists (e.g. fedotozine), and neurokinin antagonists; some of these agents are still being investigated. Understanding the brain-gut axis is crucial in the development of effective therapies for IBS.
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PMID:The brain-gut axis in irritable bowel syndrome--clinical aspects. 1517 82

This article reviews the efficacy and tolerability of traditional therapies for irritable bowel syndrome (IBS) and concludes that they are limited by both poor efficacy and adverse effects. Serotonin, a neurotransmitter found mainly in the gut, appears to represent a link in IBS pathophysiological processes -- altered gut motility, abnormal intestinal secretion and visceral hypersensitivity. Recently, available treatments for IBS have targeted serotonin receptors that are involved in motor, sensory and secretory functions of the gut. Serotonergic agents, such as alosetron (a 5-HT3 receptor antagonist) and tegaserod (a selective 5-HT4 receptor partial agonist), provide global relief of the multiple symptoms of IBS with diarrhoea and IBS with constipation, respectively, and represent important additions to the IBS treatment armamentarium.
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PMID:Options for patients with irritable bowel syndrome: contrasting traditional and novel serotonergic therapies. 1560 19

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT3 receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac, a 5-HT4 receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.
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PMID:Serotonergic modulation and irritable bowel syndrome. 1598 96

Pineal hormone melatonin is proposed as a potential treatment for severe sleep disturbances, and various gastrointestinal disorders. It was shown that melatonin increases intestinal motility and influences the activity of myoelectric complexes of the gut. The aim of the study was to evaluate the mechanisms of the effect of exogenous melatonin on gastric emptying rate. Male Sprague-Dawley rats were fitted with gastric cannulas under anesthesia. The rate of gastric emptying of saline was determined after instillation into the gastric fistula, from the volume and phenol red concentrations recovered after 5 min. Melatonin injected intraperitoneally (ip; 0.001-100 mg/kg) delayed gastric emptying rate of saline at 3 and 10 mg/kg doses. When administered ip 15 min before melatonin (10 mg/kg) injections, CCK2 (L-365,260, 1 mg/kg) or 5-HT3 receptor (ramosetrone, 50 microg/kg) blockers abolished melatonin-induced delay in gastric emptying rate, while the blockade of sympathetic ganglia (bretylium tosylate, 15 mg/kg) significantly reduced the delay in gastric emptying rate. CCK1 receptor blocker (L-364,718, 1 mg/kg) had no significant effect on the delaying action of melatonin. Our results indicate that pharmacological doses of melatonin delay gastric emptying via mechanisms that involve CCK2 and 5-HT3 receptors. Moreover, it appears that exogenous melatonin inhibits gastric motility in part by activating sympathetic neurons.
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PMID:Exogenous melatonin delays gastric emptying rate in rats: role of CCK2 and 5-HT3 receptors. 1639 13

In the gut, serotonin (5-hydroxytryptamine: 5-HT) exerts a variety of effects on intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells, which are related to the expression of multiple 5-HT receptor types and subtypes regulating motility, vascular tone, secretion and perception. Agonists and antagonists at 5-HT receptors have gained access to the market for the two major variants of the irritable bowel syndrome (IBS), a functional disorder characterized by abdominal pain associated with diarrhea and/or constipation in the absence of any organic abnormality. Indeed, the 5-HT3 receptor antagonist alosetron is available in the US market for the treatment of women with severe, diarrhea-predominant IBS (D-IBS) refractory to conventional therapy, whereas tegaserod, a partial 5-HT4 receptor agonist, has been approved by the FDA and other regulatory agencies for the treatment of women with constipation-predominant IBS (C-IBS) or functional constipation. This review is mainly intended to discuss the role of non-neuronal (paracrine) and neuronal 5-HT in the pathophysiology of functional gastrointestinal disorders (FGIDs), such as IBS and functional dyspepsia, and the mechanisms through which drugs acting on 5-HT receptors regulate visceral motility, perception and secretion in these two conditions.
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PMID:Drugs acting on serotonin receptors for the treatment of functional GI disorders. 1669 64

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.
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PMID:[Antagonists of the type 3 serotonin receptor (5 -HT3) in IBS]. 1689 18

Antineoplastic drugs have been shown to exert direct effects on the gut and induce the release of serotonin from the enterochromaffin cells of small intestinal mucosa. It is thought that released serotonin stimulates vagal afferent fibers through 5-HT3 receptors located in the vagal afferent terminals in the gastrointestinal tract and initiates sensory signals to the area postrema and the emetic center, thereby initiating nausea and vomiting. A 5-HT3 antagonist competitively inhibits serotonin at its specific binding sites, 5-HT3 receptors, and thereby elicits an antiemetic effect. Therefore 5-HT3 receptor occupancy of serotonin may be an appropriate indicator of the antiemetic activity of 5-HT3 antagonists. We analyzed 5-HT3 receptor occupancy of serotonin by integrating pharmacokinetic and receptor-binding kinetic parameters based on the receptor occupancy theory to compare the strength of the antiemetic effects of three dosage regimens of azasetron hydrochloride. The inhibitory effects on the binding of serotonin to 5-HT3 receptor of regimen 2 (an intravenous bolus injection of 5 mg of azasetron hydrochloride before and 8 h after chemotherapy) and regimen 3 (an intravenous bolus injection of 2.5 mg followed by 7.5 mg continuous intravenous infusion for 24 h) were longer-lasting than those of regimen 1 (an intravenous bolus injection of 10 mg before the start of chemotherapy). Furthermore, a positive relationship was found between the time of inhibitory effects on the binding of serotonin to 5-HT3 receptor and antiemetic effects of azasetron hydrochloride. From these results, dosage regimens 2 and 3 were considered to be more effective in the long term than regimen 1 in prophylaxis of nausea and vomiting induced by cisplatin.
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PMID:[Analysis of antiemetic effect of various dosage regimens of azasetron hydrochloride based on 5-HT3 receptor occupancy of serotonin]. 1726 55


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