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)

Part I of this article reviewed the pathophysiology of emesis, and its pharmacological treatment. Drug-induced vomiting was also discussed. In the second part of the review, other common causes of vomiting are considered. The basis of the use of antiemetics in morning sickness and migraine is still obscure; for the latter, serotonin 5-HT1 receptor agonists, 5-HT3 receptor antagonists and dopamine D2 receptor antagonists are effective. For motion sickness, control can be achieved with various antagonists of muscarinic or histamine H1-receptors. Centrally active adrenoceptor agonists in combination with a muscarinic antagonist or H1-receptor antagonist may offer better control of motion sickness and its associated symptoms than either antagonist alone; based on clinical studies, postoperative vomiting after opiate administration appears to be controlled by blocking dopamine D2, histamine H1- or muscarinic receptors. Radiation therapy appears to be similar to cytotoxic therapy in that the mediators produced or released by radiation activate both peripheral and central sites involved in the vomiting reflex. Blockade of dopamine D2 and 5-HT3 receptors may be effective.
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PMID:Pharmacological agents affecting emesis. A review (Part II). 137 13

Granisetron (BRL 43694), a selective 5-HT3 receptor antagonist, was assessed as acute therapy for the first time in migraine patients. In an open pilot study 7 migraine attacks were treated in 6 patients. All but 1 patient experienced marked and rapid relief from the headache, and nausea and vomiting were rapidly resolved in the 6 cases where these symptoms accompanied the attack. No side effects were recorded. Development of granisetron for migraine was suspended during the study for extraneous reasons.
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PMID:First clinical study of the selective 5-HT3 antagonist, granisetron (BRL 43694), in the acute treatment of migraine headache. 165 Mar 35

Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT3 receptor in radiolabeled ligand-binding studies, and have shown 5-HT3 receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT3 antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT3 receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT3 recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT3 receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two "binding shapes" or "active shapes" for 5-HT3 ligands have been identified from detailed conformational analyses.
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PMID:Molecular modeling of 5-HT3 receptor ligands. 181 57

1. A number of serotonergic agents have been shown to be effective in the treatment of migraine. At the present time, migraine drug interactions have been analyzed most extensively at 5-hydroxytryptamine1D (5-HT1D), 5-HT2 and 5-HT3 receptor subtypes. 2. This review will summarize the current status of 5-HT receptor subtypes as they relate to anti-migraine agents. 3. The available data suggest that drug interactions with specific 5-HT receptor subtypes may be the basis for their efficacy in both the acute and prophylactic treatment of migraine.
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PMID:New vistas on 5-HT receptors and migraine. 187 21

Neuronal 5-hydroxytryptamine3 (5-HT3) receptors mediate the excitatory effects of 5-HT. They are located in pain- and nausea-modulating areas in the central nervous system and on C-fibre primary afferents in the peripheral nervous system. Consequently, these receptors mediate the painful and emetic effects of 5-HT. Selective and potent 5-HT3 receptor antagonists have been shown to block inflammatory and 5-HT induced and potentiated "vascular pain". Based on the hypothesis that 5-HT3 receptor antagonists may block neurogenic dural inflammation in the distribution area of the trigeminal nerve and, thus, could potentially prevent migraine (pain), four highly selective and potent 5-HT3 receptor antagonists have been tested in both the acute and prophylactic treatment of migraine. Unfortunately, except for a clear anti-emetic effect, none of these drugs has shown unequivocal efficacy in the treatment of migraine. This may be partly due to the complex (bell-shaped) dose-response relationship of these compounds, making exact titration of the correct dose difficult. Moreover, most 5-HT3 receptor antagonists have proved to be toxic in man on chronic administration thereby preventing further trials in migraine with adjusted doses. Short-term treatment for cytotoxic drug-induced emesis so far appears to be the only proven indication for 5-HT3 receptor antagonists.
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PMID:5-HT3 receptor antagonists and migraine therapy. 204 32

Chemotherapy-induced emesis is one of the major problems in the treatment of oncologic patients. Recently, a novel class of compounds, the selective 5HT3 receptor antagonists, has been introduced, achieving a dramatic improvement in the control of emesis. The absence of extrapyramidal side effects adds to their safety and good tolerability. The Authors herein analyse their experience on 269 cycles of chemotherapy in 47 patients treated for gynaecological and breast malignancies, with particular regard to adverse events such as headache. Their most frequent side-effects are headache and constipation, that are usually mild and self-limiting. Nevertheless, in some cases, severe, rebel headache has been reported, leading in our experience in 6.4% of cases to discontinuation of the antiemetic regimen. A previous history of recurrent or severe headache or migraine is not correlated with the occurrence of ondansetron-induced headache, as severe headache occurred after ondansetron only in 28.4% of the patients with positive anamnesis, and 70% of the patients that experienced had never suffered from severe headache before. In those patients complaining of severe headache, the Authors suggest an antiemetic association, with a loading dose of ondansetron i.v., followed by metoclopramide i.m. orally for the following days.
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PMID:Ondansetron-induced headache. Our experience in gynecological cancer. 766 68

The pharmacology of 5-HT and the classification of 5-HT receptors have become increasingly complex. However, recent advances have produced a new nomenclature system for 5-HT receptors. 5-HT3 receptors are neuronal receptors coupled directly to cation channels. Recently, many selective 5-HT3-receptor antagonists including tropisetron, zacopride, ondansetron, granisetron, zatosetron, nazasetron, YM060 and YM114 (KAE-393) have been developed. Many actions attributable to the 5-HT3-receptor have been described in both the peripheral and central nervous systems, and clinical trials are already showing the potential use of these 5-HT3 receptor antagonists in a number of disorders of the gastrointestinal tract and central nervous system, such as nausea and vomiting induced by cancer chemotherapy, anxiety, depression, schizophrenia and migraine. In addition, endogenous 5-HT is suggested to be one of the substances that mediate stress-induced responses in gastrointestinal function, i.e., increase in fecal pellet output and diarrhea. Moreover, YM060, YM114 (KAE-393) and granisetron have been reported to inhibit restraint stress- and 5-HT-induced increases in fecal pellet output and diarrhea in rats and mice, indicating that endogenous 5-HT may mediate stress-induced changes in bowel function through the 5-HT3 receptor. Therefore, 5-HT3-receptor antagonists are new therapeutic drugs for stress-induced gastrointestinal dysfunctions like irritable bowel syndrome (IBS).
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PMID:[Serotonin (5-HT)3 receptors: antagonists and their pharmacological profiles]. 795 7

Zatosetron (13 mg or 0.19 mg/kg), a potent and selective 5-HT3 receptor antagonist was studied with a 30 min infusion in a crossover double-blind placebo-controlled trial for acute migraine therapy. Groups receiving zatosetron and placebo were demographically similar and zatosetron was well-tolerated in all patients with no clinically significant adverse effects. Migraine severity was reduced in both the placebo and zatosetron groups with no statistically significant differences between zatosetron and placebo. Likewise, no statistically significant differences between placebo and zatosetron treatment groups were identified with regard to migraine duration, overall migraine severity or the relief medication required. Although several limitations of this study exist, these data documenting a lack of benefit of intravenously-administered zatosetron in alleviating the acute pain of migraine add to the list of 5-HT3 receptor antagonists that have failed to support efficacy of this therapeutic modality in the acute treatment of migraine.
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PMID:Zatosetron, a 5-HT3 receptor antagonist in a multicenter trial for acute migraine. 798 90

There has been tremendous interest in 5-HT3 receptor antagonists since their discovery and the subsequent identification of 5-HT3 receptors in the CNS. Based on the results of early behavioural tests with these compounds, there has been substantial interest in their potential use for the treatment of various CNS disorders. In this review, Andrew Greenshaw attempts to clarify the status of the therapeutic potential of these drugs, discussing inconsistencies in preclinical findings and identifying areas in need of clarification through future research. 5-HT3 receptor antagonists are claimed to be potentially useful in the treatment of nausea, inflammatory pain (migraine and irritable bowel syndrome), anxiety, depression, schizophrenia, dementia and drug abuse!
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PMID:Behavioural pharmacology of 5-HT3 receptor antagonists: a critical update on therapeutic potential. 810 96

This article reviews the pathophysiology and pharmacology of emesis in relation to migraine pathogenesis. Also, the place of antiemetic and gastrointestinal prokinetic agents in current and future acute migraine treatment strategies is reviewed. The mechanisms of action of current and novel acute migraine therapies are considered with respect to the neurogenic and vascular hypothesis. Control of migraine-associated nausea and vomiting is often achieved with the benzamide dopamine D2 receptor antagonist metoclopramide. This drug also has 5HT3 receptor antagonist activity and reproducibly stimulates gastric motility to increase the availability of orally administered drugs. Other antiemetic and gastroprokinetic agents with potential value for the treatment of migraine-associated nausea and vomiting could speed absorption of oral antimigraine therapies without central nervous system side effects. Domperidone, a dopamine D2 receptor antagonist that does not cross the blood brain barrier is relatively free of the central side-effect liability of metoclopramide. Cisapride, a benzamide 5HT4 receptor agonist gastrointestinal prokinetic drug, lacks dopamine antagonist activity. A controlled comparison of these agents as migraine co-therapies could provide information on the importance of peripheral and central mechanisms in migraine-associated nausea and vomiting and improve antimigraine treatment options.
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PMID:Pathophysiology and pharmacology of migraine. Is there a place for antiemetics in future treatment strategies? 987 82


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