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)

This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.
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PMID:Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides. 131 2

1. The aim of the present study was to examine the effect of 5-hydroxytryptamine (5-HT) on K+ current in primary culture of mouse colliculi neurones and to identify the 5-HT receptor subtype that could be involved in this effect. 2. The voltage-activated K+ current of the neurones was partially blocked by 8-bromo adenosine 3':5'-cyclic monophosphate (8-bromo-cyclic AMP). This effect was mimicked by 5-HT and the action of 5-HT could be antagonized by H7, a non specific protein kinase inhibitor, and by PKI, the specific cyclic AMP-dependent protein kinase blocker. 3. A similar cyclic AMP-dependent blockade of the K+ current was found with renzapride (BRL 24,924) and other 5-HT4 receptor agonists such as cisapride, BIMU 8, zacopride and 5-methoxytryptamine (5-MeOT). ICS 205,930, the classical 5-HT4 receptor blocker, could not be used in this study because it inhibited the studied K+ current by itself. However, the novel 5-HT4 receptor antagonist, DAU 6285 blocked the effects of 5-HT and renzapride on the K+ current. 4. The current was insensitive to the 5-HT1 and 5-HT3 receptor agonists (8-hydroxy-2-(di-n-propylamino) tetralin, RU 24,969, carboxamidotryptamine, 2-CH3-5-HT) as well as to 5-HT1, 5-HT2 and 5-HT3 antagonists (methiothepin, ketanserin, ondansetron [GR 38,032]). Moreover, these antagonists did not affect the actions of the tested 5-HT4 receptor agonists. 5. The present results show that part of the voltage-activated K+ current in mouse colliculi neurones is cyclic AMP-sensitive and the blockade of the current by 5-HT involves the 5-HT4 receptor subtype.The putative implication of 5-HT4 receptors in neuronal plasticity, via a blockade of K+ channels, is discussed.
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PMID:The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase. 132 59

The effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066 B and RU 24969, the 5-HT1A/1B antagonist (+/-)pindolol, the 5-HT2/1C receptor antagonist ritanserin, the 5-HT2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT3 receptor antagonist BRL 43694, the unselective 5-HT receptor antagonist methiothepin, and carbidopa + L-5-hydroxytryptophan (L-5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethyl-phenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%-220% of controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo. 132 93

Adult male CD1 mice received the 5-HT3 receptor antagonist, BRL 46470A, by intraperitoneal injection at three dose levels (2.5 mg/kg, 25 and 2.5 micrograms/kg). Controls were injected with physiological saline. At 30 min after injection, the behaviour of each mouse was examined by ethological procedures, when encountering an untreated partner for 5 min in its home cage and for 5 min in the more aversive situation of an unfamiliar neutral cage. The behaviour of each mouse also was monitored for 5 min in a two compartment light-dark box. At all doses tested, BRL 46470A increased the time spent in the light compartment of the light-dark box. At the smallest dose (2.5 micrograms/kg), the number of transitions between light and dark compartments was increased and there also was an increase (per unit time) in the numbers of squares crossed and number of scans in the light compartment. At all doses tested, BRL 46470A increased social investigation and reduced non-social exploratory activity in both the home cage and the unfamiliar neutral cage. In both test situations, increase of social investigation was maximum at 25 micrograms/kg, and at this dose, aggressive behaviour was also enhanced. In the neutral cage, digging in the sawdust by drug-treated mice showed a progressive dose-related increase. These results indicate potent anxiolytic-like activity by BRL 46470A and also demonstrate increased reactivity to unfamiliar environmental stimuli, such as novel sawdust. The significance of these findings is discussed.
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PMID:Effects of acute administration of the 5-HT3 receptor antagonist, BRL 46470A, on the behaviour of mice in a two compartment light-dark box and during social interactions in their home cage and an unfamiliar neutral cage. 135 51

In the present study, the effects of 5-HT and two 5-HT1c/5-HT2 receptor agonists, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and alpha-methyl-serotonin (alpha-Me-5-HT) on phosphoinositide hydrolysis were compared, to determine whether DOI and alpha-Me-5-HT were full agonists. Consistent with the results obtained from previous studies, both (+/-)-DOI and alpha-Me-5-HT stimulated turnover of phosphoinositide in a concentration-dependent manner. However, the response obtained with these 5-HT1c/5-HT2 receptor agonists was only 30-40% of that of 5-HT. The stimulation of hydrolysis of phosphoinositide, produced by both 5-HT2 receptor agonists, was potently antagonized by ritanserin (a 5-HT1c/5-HT2 receptor antagonist) and alpha-phenyl-1-(2-phenylethyl)-4-piperine methanol [(+)-MDL 11,939, a 5-HT2 receptor antagonist] but not by granisetron (BRL a 5-HT3 receptor antagonist), suggesting that the action of DOI and alpha-Me-5-HT was primarily mediated by 5-HT2 receptors. When the effect of increasing the concentration of 5-HT on turnover of phosphoinositide was measured in the presence of a 1 microM concentration of the 5-HT3 receptor antagonist granisetron, the response obtained was similar to the response produced by the 5-HT2 receptor agonists, DOI and alpha-Me-5-HT. These results confirm the previous finding that 5-HT stimulates hydrolysis of phosphoinositide by interacting with 5-HT1c/5-HT2 and 5-HT3 receptors. Moreover, they suggest that DOI and alpha-Me-5-HT are full agonists at the 5-HT2 receptor, coupled to hydrolysis of phosphoinositide in the cortex of the rat.
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PMID:(+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane(DOI) and alpha-methyl-5-HT: 5-HT2 receptor agonistic action on phosphatidylinositol metabolism in the rat fronto-cingulate and entorhinal cortex. 140 1

Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.
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PMID:Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides. 154 79

Chlordiazepoxide (21.5 mg/l; 5 mg/kg daily), buspirone (12.8 g/l; 3.4 mg/kg daily) and the 5-HT3 receptor antagonist, BRL 46470, (40 micrograms/l; 10 micrograms/kg daily) were each given in the drinking fluid for 12-14 days to adult male CD1 mice. Controls received tap water. Effects of the treatments on behaviour during 5 min social encounters with untreated partners were examined by ethological procedures in an aversive and less aversive situation, an unfamiliar neutral cage and the home cage. In the neutral cage all compounds increased the occurrence of the social act, "nose" and enhanced digging of the unfamiliar sawdust, at the expense of exploration. In the home cage, all compounds increased social investigation and reduced non-social activity. The drug BRL 46470 evoked more marked effects on behaviour than did buspirone or chlordiazepoxide and in the neutral cage it enhanced some acts of aggression. These results show that all compounds increased reactivity to normal social and environmental stimuli, in addition to their anxiolytic profile of behavioural effects.
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PMID:Effects of sub-chronic treatment with chlordiazepoxide, buspirone and the 5-HT3 receptor antagonist, BRL 46470, on the social behaviour of mice. 163 May 89

Buspirone (12.8 mg/l; 2.3-2.6 mg/kg daily) and the 5-HT3 receptor antagonist, BRL 43694 (granisetron) (40 micrograms/l; 10 micrograms/kg daily), were each given in drinking fluid to male and female DBA/2 mice for 5-10 days. Controls received tap water. Effects on behaviour were examined by ethological procedures during 5 min encounters with unfamiliar BKW partners. One group of DBA/2 males acted as intruders in a resident-intruder paradigm and another group encountered oestrous females in a neutral cage. The DBA/2 females each encountered a group-housed male in a neutral cage. Both buspirone and BRL 43694 decreased flight in females and increased the duration of their active social investigation. In females, BRL 43694 also reduced the occurrence of "scan" and prolonged the bout length of exploration. In male mice, buspirone increased social investigation, including the specific elements "sniff" and "follow" in encounters with female partners, but its only effect on behaviour during encounters with isolated resident males, was to decrease duration of the element, "attend". In males, BRL 43694 did not significantly affect behaviour in heterosexual encounters and had only a slight effect on behaviour during encounters with resident males, decreasing the occurrence of "eat". Overall, these results suggest that records of effects of drugs on flight responses of female mice, in encounters with male partners, may provide a sensitive index of the anxiolytic profile of novel compounds.
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PMID:An ethological study of the effects of buspirone and the 5-HT3 receptor antagonist, BRL 43694 (granisetron) on behaviour during social interactions in female and male mice. 164 17

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

Trials of selective 5-hydroxytryptamine3 receptor antagonists have shown excellent antiemetic activity for chemotherapy containing cisplatin when compared with high-dose metoclopramide. There is little information about the efficacy of these new agents for chemotherapy other than for high-dose cisplatin. We performed a double-blind, randomized trial comparing a single dose of the 5-hydroxytryptamine3 receptor antagonist granisetron (BRL 43694A) as a single intravenous dose with dexamethasone plus prochlorperazine in 152 patients receiving their first course of moderately emetogenic chemotherapy (mainly doxorubicin- and cyclophosphamide-containing combinations). During the first 24 hours, there was a statistically significant advantage for the granisetron group in terms of the prevention of both nausea and emesis. There was no difference in the frequency of reported adverse events. We conclude that granisetron is more effective than dexamethasone plus prochlorperazine in patients who are receiving moderately emetogenic cytotoxic agents.
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PMID:Superiority of granisetron to dexamethasone plus prochlorperazine in the prevention of chemotherapy-induced emesis. 165 63


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