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

The serotonin 5-HT3 receptor antagonist effects of zacopride and its optical isomers were evaluated in rats trained to discriminate 5.0 mg/kg of 2-methylserotonin (2-Me 5-HT) from saline in a 2-lever operant task. Zacopride and its enantiomers potently antagonized the 2-Me 5-HT stimulus; on the basis of 50% inhibition (ID50) of drug lever responding the order of potency is S(-)-zacopride (ID50 = 0.05 micrograms/kg) greater than (+/-)-zacopride (ID50 = 0.60 micrograms/kg) greater than R(+)-zacopride (ID50 = 1.6 micrograms/kg). The stereoselectivity and potency ratio of zacopride's isomers for antagonizing the 2-Me 5-HT stimulus parallels their previously reported results in binding studies. It is concluded that zacopride's isomers produce antagonism of a 2-Me 5-HT stimulus by stereoselective interaction at 5-HT3 receptors and that stereochemical factors are important in evaluating the stimulus properties of 5-HT3 agents.
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PMID:Zacopride and its optical isomers produce stereoselective antagonism of a 2-methylserotonin discriminative stimulus. 155 33

Recent experimental data, both in animals and the clinic, suggest that drugs selectively interacting with the 5-HT system may reduce alcohol intake. Although the precise mechanisms underlying these drug effects are unknown, it seems that there are at least two pharmacological strategies available, described in this review by Edward Sellers and colleagues. The first is enhancement of 5-HT neuronal activity using compounds that will release 5-HT, block 5-HT reuptake, or act as selective 5-HT receptor agonists. A second approach involves selective 5-HT3 receptor antagonists. If the initial research findings with these drugs are confirmed and extended, they may present useful therapies for the treatment of alcohol abuse, especially if used in conjunction with psychosocial therapy.
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PMID:5-HT and alcohol abuse. 156 16

Evidence is reviewed that 5-HT (5-hydroxytryptamine, serotonin) acting through the 5-HT3 receptor subtype can influence behaviour relevant to anxiety, schizophrenia and cognitive disorders, and that 5-HT3 receptor antagonists such as ondansetron (CAS 116002-70-1) can correct behavioural disturbance in the absence of effect on normal behaviour. The 5-HT3 receptor antagonists exert a breadth of action over a wide dose range in rodent and primate models to inhibit aversive behaviour in animal models of anxiety and certain symptoms of withdrawal from drugs of abuse, alcohol, nicotine, diazepam and cocaine, to antagonise increased locomotor activity caused by mesolimbic dopamine excess, and facilitate performance in cognitive tests. The studies reveal an important role for 5-HT3 receptors in the regulation of limbic-cortical functioning, and a critical role for 5-HT3 receptor antagonists to establish the role of 5-HT3 receptors in schizophrenia, anxiety, drug withdrawal phenomena and cognitive disturbance. Preliminary clinical trials indicate a positive effect of ondansetron in anxiety, schizophrenia, alcohol withdrawal and age associated memory impairment.
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PMID:Serotonin and psychiatric disorders. A key to new therapeutic approaches. 158 95

Rac-ML-1035 (MDL 201,035: 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl] benzamide hydrochloride) is a racemic gastroprokinetic with serotonergic (5-hydroxytryptamine, 5-HT) activity and a novel chiral sulfoxide substituent. Chromatographic and chemical methods have been developed to resolve the enantiomers of rac-ML-1035, and the absolute configuration of the (R)-enantiomer has been determined. We also report pharmacological characterization of rac-ML-1035 and its respective isomers. Radioligand binding to rat cortical membranes revealed that (R)-ML-1035 (MDL 201,226) and (S)-ML-1035 (MDL 201,227) had equivalent activity at the 5-HT3 receptor. However, in isolated tissue studies including field-stimulated guinea pig ileum, field-stimulated rat fundic strip, and nonstimulated guinea pig ileum, (S)-ML-1035 was equally potent yet had greater maximal activity than (R)-ML-1035 in eliciting or facilitating cholinergic contractions. Thus, enantiomers of rac-ML-1035 can be resolved, and the relative configuration of these isomers influences their pharmacological activity.
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PMID:The resolution, isolation, and pharmacological characterization of the enantiomers of a benzamide containing a chiral sulfoxide. 158 86

Serotonin (5-hydroxytryptamine; 5-HT) is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function. A number of receptor or recognition sites have been identified in the gut, but recently most attention has focused on the 5-HT3 and 5-HT4 receptors. The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut. A number of selective 5-HT3 antagonists have been developed including ondansetron, granisetron, tropisetron renzapride and zacopride. While the substituted benzamide prokinetics (for example, metoclopramide, cisapride) also block 5-HT3 receptors in high concentrations, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptor. Some 5-HT3 antagonists have 5-HT4 agonist activity (for example, renzapride, zacopride) and others do not (for example, ondansetron, granisetron), while tropisetron in high concentrations is a 5-HT4 antagonist. Based on the pharmacological data, it has been suggested that specific 5-HT antagonists and agonists may prove to be beneficial in a number of gastrointestinal disorders including the irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, gastrooesophageal reflux and refractory nausea. In this review, the rationale for the use of these compounds is discussed, and the available experimental evidence is summarized.
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PMID:Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. 160 46

We examined ethanol's interactions with serotonin (5-HT) receptor-mediated [3H]5-HT high-affinity uptake by adult rat forebrain synaptosomes. The serotonergic transport mechanism was chosen because ethanol consumption patterns can be manipulated by serotonin receptors and uptake blockers. We report that a dose of ethanol which causes general anesthesia in humans (54 mM) applied in vitro enhanced rat synaptosomal [3H]5-HT uptake after 5 min at 37 degrees C. Similar levels of stimulation by 54 mM ethanol were seen in hippocampal, cerebral cortex and brainstem synaptosomes. Significant inhibition of uptake was not detected until concentrations of ethanol reached 2.1 M, which is lethal in vivo. Ryanodine and the 5-HT2 agonist, DOI, are believed to cause an increase in intracellular Ca2+ levels. We observed that they also caused an elevation of [3H]5-HT uptake, and this stimulation was less than additive with the ethanol-induced increase. Inhibition of the 5-HT3, receptor-mediated Na+ channel with the antagonist ICS 205930, partially reversed ethanol's stimulatory effects on [3H]5-HT uptake. Blockade of voltage-dependent Na+ flux with tetrodotoxin and lidocaine, however, had no effect on the stimulation by ethanol. But tetraethylammonium, which blocks voltage-dependent K+ channels, partially counteracted ethanol's action on [3H]5-HT uptake. These compounds had no effect on uptake by themselves. These results indicate that ethanol's stimulation of [3H]5-HT uptake involves a rise in [Ca2+]i which is sensitive to voltage-dependent K+ flux and 5-HT3 receptor-mediated Na+ flux, and would decrease the availability of synaptic 5-HT.
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PMID:Ethanol stimulates [3H]5-HT high-affinity uptake by rat forebrain synaptosomes: role of 5-HT receptors and voltage channel blockers. 164 10

1. Tight-seal voltage-clamp techniques were used to study the 5-HT3 receptor of differentiated NG108-15 cells. 2. The inward current caused by 5-HT was dependent on the 5-HT concentration: the apparent dissociation constant was 3.3 microM and the Hill coefficient was 1.8. 3. Immediately after establishing a recording, sustained application of a saturating concentration of 5-HT caused the response to decline with a half-time of 0.57 s (at a membrane potential of -70 mV). The time course of desensitization was best fitted by a sum of two exponentials. 4. Desensitization became slower during the first 10 min of recording in the whole-cell configuration, with the half-time for response decay increasing to 1.8 s. The deceleration of desensitization may result from wash-out of a cytoplasmic regulator of the receptor. 5. Desensitization declined less during whole-cell recordings when patch pipettes contained non-hydrolysable analogues of adenosine 5'-triphosphate. 6. Desensitization developed more rapidly following the addition of forskolin, prostaglandin E1, cholera toxin or 1,9-dideoxyforskolin to the recording medium. Non-hydrolysable adenosine 5'-phosphate analogues had no effect on the enhancement of desensitization induced by forskolin.
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PMID:Activation and desensitization of the 5-HT3 receptor in a rat glioma x mouse neuroblastoma hybrid cell. 164 31

DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) significantly depressed end plate current (EPC) amplitude. It decreased quantum content, increased the extent of neurally evoked EPC rundown during the train, produced a nonlinear current-voltage relationship, shortened time constant of decay, and depressed iontophoretically evoked EPC. The depressant response of DOI on EPC amplitude was antagonized by 5-HT1-like receptor antagonists, but was resistant to 5-HT2 and 5-HT3 receptor antagonists. This suggests that inhibitory 5-HT receptors roughly correspond to 5-HT1-like receptors.
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PMID:Effect of (+/-)-DOI on neuromuscular transmission: a microelectrode study. 164 93

Radiotherapy-induced emesis is poorly controlled with existing antiemetics. 5-Hydroxytryptamine (5HT3) receptor antagonists are a new class of antiemetics which have been demonstrated to be effective in controlling cytotoxic-induced emesis. We have prospectively studied the antiemetic efficacy of the 5HT3 receptor antagonist granisetron in an open non-randomized efficacy and toxicity study, at two dose levels, in patients receiving lower hemibody radiotherapy for multiple bone metastases. Of the 22 patients studied, 13 patients received 20 micrograms/kg and nine patients 40 micrograms/kg of granisetron, administered as an intravenous infusion 1 h before radiotherapy. Radiotherapy was administered as a single exposure to the lower half body to a midline dose of 8 Gy. A complete response (no nausea or vomiting) was observed in 9/13 patients at the lower dose level and 6/9 patients at the higher level. No major adverse events were recorded. We conclude that granisetron is a well-tolerated and effective antiemetic agent in radiotherapy-induced emesis. Formal comparison with conventional antiemetic agents in this situation is required.
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PMID:The antiemetic effect of granisetron in lower hemibody radiotherapy. 165 14

The effects of various 5-HT3 receptor antagonists were examined in the social interaction (SI) test following discrete microinjection into either the dorsal raphe nucleus (DRN) or amygdala of the rat. Following DRN injection, ondansetron, ICS205-930, and MDL72222 (5-500 ng) all failed to modify SI under high light/unfamiliar (HLU) test conditions relative to vehicle pretreated controls. The 5-HT3 receptor agonist, 2-Me 5-HT (100-2500 ng), was similarly ineffective under both HLU and low light/familiar (LLF) conditions, although 5-HT (20-100 ng) increased SI under the HLU paradigm. After amygdaloid injection, ondansetron (10-100 ng), granisetron (1-10 ng), ICS205-930 (10-100 ng), GR 65630 (1-10 ng), and MDL72222 (100-1000 ng) all significantly increased SI under the HLU but not LLF condition. Furthermore, a detailed behavioural analysis revealed that the behaviours underlying this increase were similar to those seen in vehicle pretreated animals tested in the LLF compared to HLU condition. The benzodiazepine, flurazepam (200 ng), increased both SI (HLU condition) and punished responding in a modified water-lick conflict model, after amygdaloid injection. Both ondansetron (10-1000 ng) and ICS205-930 (1-100 ng) were ineffective in the conflict test. Finally, 2-Me 5-HT and 5-HT (100-10,000 ng) reduced SI under the LLF test condition with no concomitant change in locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence that the amygdala is involved in the disinhibitory effects of 5-HT3 receptor antagonists. 166 12


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