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)

Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3-5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 micrograms/kg, i.v.). No significant binding (Ki greater than 10 mumol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic alpha 1, alpha 2, dopaminergic D1, D2 or muscarinic M1-M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.
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PMID:Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285. 132 Feb 4

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

1. An excitatory response to 5-hydroxytryptamine (5-HT) was measured from the afferent vagus nerve of anaesthetized rats. Measurements were determined by an extracellular recording from the whole nerve. 2. Intravenous bolus injection of 5-HT (1.56-100 micrograms kg-1) evoked a dose-dependent excitation of afferent vagus nerve activity. This response was blocked not only by a selective 5-HT3 receptor antagonist, GR38032F (10 and 100 micrograms kg-1), but also by a 5-HT2 receptor antagonist, ketanserin (10 and 100 micrograms kg-1). 3. Both a 5-HT3 receptor agonist, 2-methyl-5-HT (3.12-100 micrograms kg-1), and a 5-HT2 receptor agonist, alpha-methyl-5-HT (3.12-50 micrograms kg-1), produced a dose-dependent excitation of afferent vagus nerve activity. These excitatory effects were antagonized by GR38032F (10 micrograms kg-1) and ketanserin (10 micrograms kg-1), respectively. 4. A 5-HT1 like receptor agonist, 5-carboxamidotryptamine (50 micrograms kg-1), and a putative 5-HT4 receptor agonist, 5-methoxytryptamine (100 micrograms kg-1), failed to produce excitatory effects on the afferent vagus nerve. 5. These results suggest that the 5-HT-induced excitatory response of the afferent vagus nerve might be mediated not only via 5-HT3 receptors but also via 5-HT2 receptors in anaesthetized rats. It is unlikely, however, that either 5-HT1-like or putative 5-HT4 receptors are involved in the excitatory response of the afferent vagus nerve to 5-HT.
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PMID:Pharmacological characterization of 5-hydroxytryptamine-induced excitation of afferent cervical vagus nerve in anaesthetized rats. 138 26

The effect of antagonists of serotonin (5-HT) receptor subtypes and alpha 2-adrenoceptors was investigated on audiogenic seizures and locomotor activity in DBA/2 mice. 5HT1c receptor antagonists (mianserin and cyproheptadine), 5-HT3 receptor antagonist (zacopride) and 5-HT4 receptor antagonist (ICS 205-930) increased the latency of audiogenic seizures and decreased the severity of convulsions in young (20-27 days old) DBA/2 mice. However, the effect of these antagonists varied in older (30-37 days old) mice. Ketanserin, 5-HT2 receptor antagonist, was devoid of any activity on audiogenic seizures. Yohimbine (0.5 mg/kg, i.p.), an alpha 2-adrenoceptor antagonist, increased the severity of audiogenic seizures, and the anti-convulsant effect of 5-HT receptor subtypes antagonists became more pronounced in the presence of yohimbine. 5-HT3 and 5-HT4 receptor antagonists produced hypolocomotor activity in young mice whereas 5-HT1c and 5-HT2 receptor antagonists were devoid of any effect on locomotor activity. Yohimbine did not induce any effect on locomotor activity but the mice exhibited more pronounced hypolocomotor activity following the administration of 5-HT3, 5-HT4 and 5HT1c receptor antagonists in the presence of yohimbine. However, the results varied with these agents in the older mice. These observations implicate a role of 5-HT1c, 5-HT3, 5-HT4 and alpha 2-adrenoceptors in audiogenic seizures in young DBA/2 mice, and 5-HT3 and 5-HT4 receptors in locomotor activity in these mice. Furthermore, these results also suggest an interaction between 5-HT receptors and alpha 2-adrenoceptors, and differential development patterns of various 5-HT receptor subtypes in the CNS.
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PMID:Effects of 5-HT receptor antagonists on seizure susceptibility and locomotor activity in DBA/2 mice. 139 77

This study describes a component of 5-HT-evoked depolarization of the rat isolated vagus nerve which was unaffected by the 5-HT3 receptor antagonist ondansetron. A grease-gap extracellular recording technique was used. Ondansetron (10-100 nmol/l) displaced the 5-HT concentration-response curve to the right yielding a pA2 value of 8.6 (8.5-8.8), consistent with 5-HT3 receptor antagonism, and revealing a component of the 5-HT response which was resistant to ondansetron blockade. In the presence of ondansetron (100 nmol/l) the maximum depolarization in the resistant phase was 15.5 (12.6-19.2)% of the initial maximum response to 5-HT and the pEC50 value was 7.0 (6.7-7.3). The mechanism of the ondansetron-resistant component of the 5-HT response resembled a 5-HT4-receptor-effect in being absent in preparations equilibrated with 5-methoxytryptamine (10 mumol/l) and antagonised by ICS 205930 (tropisetron, pA2 6.4). 5-Methoxytryptamine alone was an agonist in the vagus nerve with a maximum response similar to that of the ondansetron resistant phase of the 5-HT response. Similarly renzapride alone evoked small depolarizations of this preparation but antagonized the ondansetron resistant phase of the 5-HT response (pA2 7.3-7.4). These effects of 5-methoxytryptamine and renzapride are also consistent with a 5-HT4 receptor mechanism. Ketanserin (1 mumol/l) and methysergide (1 mumol/l) had little effect on responses to 5-HT. The depolarization evoked by this putative 5-HT4 receptor mechanism was small but prolonged and appears to mask and after-hyperpolarizing phase of the 5-HT response in this tissue.
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PMID:A component of 5-HT-evoked depolarization of the rat isolated vagus nerve is mediated by a putative 5-HT4 receptor. 147 Feb 21

The influence of three azabicycloalkyl benzimidazolone derivatives, DAU 6236, BIMU 1 and BIMU 8, which act as agonists at central 5-hydroxytryptamine (5-HT)4 receptors, has been investigated on cholinergic neuromuscular transmission and peristalsis in the guinea pig small intestine. In the longitudinal muscle myenteric plexus preparations, these compounds caused a concentration-dependent (range 1-300 nM) enhancement of the amplitude of nerve-mediated cholinergic submaximal contractions to electrical stimulation. In comparison to the potentiating effect of 5-methoxytryptamine (a reference 5-HT4 receptor agonist), the rank order of agonist potency was BIMU 8 = BIMU 1 greater than DAU 6236 = 5-methoxytryptamine. In whole ileal segments, DAU 6236, BIMU 1 and BIMU 8 increased markedly (maximum increase, 200%) the frequency of peristalsis within the range of 0.1 to 3 microM. Micromolar concentrations of ICS 205-930, which is a low affinity antagonist of 5-HT4 receptors, were required to antagonize the facilitatory effect on cholinergic transmission caused by benzimidazolone derivatives and 5-methoxytryptamine (pA2 values, 6.5 in average) and to reverse the increase in the frequency of peristalsis induced by DAU 6236, BIMU 1 and BIMU 8. By contrast, the potent and selective 5-HT3 receptor antagonist ondansetron (1 microM) was ineffective. Our findings indicate that benzimidazolone derivatives act as agonists in the guinea pig ileum causing enhancement of acetylcholine release and peristaltic activity. The neural receptor site involved in the action of benzimidazolone derivatives and which showed low affinity for ICS 205-930 is probably identical to the putative 5-HT4 receptor subtype agonized by indoleamines and substituted benzamide derivative prokinetic agents.
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PMID:Benzimidazolone derivatives: a new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum. 157 56

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

Previous studies of the mechanism of zacopride-induced emesis in ferrets have concluded that it is mediated predominantly by an antagonist effect on 5-HT3 receptors although the possibility of a contribution from an agonist effect at 5-HT4 receptors was not excluded. This study shows that zacopride (200 micrograms/kg p.o.)-induced emesis can be blocked by a 'high dose' (1000 micrograms/kg) of ICS205930 but not by a low dose (100 micrograms/kg) or by 'high doses' (1000 micrograms/kg) of another more selective 5-HT3 receptor antagonist granisetron. As ICS205930, at high doses, is reported to be a 5-HT4 receptor antagonist it appears likely that activation of 5HT4-receptors contributes to emesis induced by zacopride. 'High' doses of ICS205930, but not granisetron or ondansetron, can also block the vagally mediated emesis induced by oral CuSO4 suggesting that 5-HT4 receptors involved in emesis are closely associated with abdominal vagal afferents.
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PMID:Preliminary evidence for the involvement of the putative 5-HT4 receptor in zacopride- and copper sulphate-induced vomiting in the ferret. 166 56

1. An investigation has been made into the 5-hydroxytryptamine (5-HT) receptor mediating relaxation of rat oesophagus in preparations precontracted with carbachol. 2. In tissues treated with pargyline (100 microM) and in the presence of corticosterone (30 microM) and cocaine (30 microM) the potency of 5-HT and 5-methoxytyramine (5-MeOT) was not changed but the maximum response to these agonists was reduced. Thus there was no evidence of metabolism and/or uptake through an amine depleting mechanism. 3. The relaxant concentration-effect curves to 5-HT were shifted to the left in a concentration-related manner by isobutylmethylxanthine (1 and 10 microM), suggesting the involvement of adenosine 3':5'-cyclic monophosphate in these responses. 4. 5-HT produced concentration-related relaxations of rat oesophagus with an EC50 value of 0.24 microM. Several indole agonists were tested and the following rank order of potency of key agonists obtained: 5-HT greater than alpha-methyl-5-hydroxytryptamine = 5-carboxamidotryptamine (5-CT) greater than 5-MeOT. In contrast, 2-methyl-5-hydroxytryptamine, sumatriptan and 8-hydroxy-2-(di-n-propylamino) tetralin were weak or inactive. 5. The substituted benzamides, metoclopramide, cisapride, renzapride and R,S-zacopride acted as partial agonists, producing 60-70% of the 5-HT maximum. 6. The relaxation responses to 5-HT were neither inhibited by antagonists selective for 5-HT1 or 5-HT2 receptors nor by the 5-HT3 receptor antagonists, ondansetron, granisetron or MDL 72222. 7. The relaxation responses induced by 5-HT, 5-CT, 5-MeOT and renzapride were selectively inhibited by high concentrations of ICS 205-930 with pKB values of approximately 6. 8. The 5-HT receptor mediating relaxation in rat oesophagus cannot be designated 5-HT1, 5-HT2 or 5-HT3 under the current 5-HT classification, but the observed effects are consistent with stimulation of the putative 5-HT4 receptor.
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PMID:Investigation into the 5-hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus. 187 46

The effects of cisapride on intestinal contractility and on release of acetylcholine (ACh) were examined using the longitudinal muscle with the myenteric plexus preparation from the guinea pig ileum, as related to the 5-hydoxytryptamine (5-HT) receptor. 5-HT exerted a dual effect, transient increase in ACh release (EC50 = 2 X 10(-6)M) via the 5-HT3 receptor, followed by inhibition (EC50 = 5 X 10(-9)M) via the 5-HT1 receptor. Cisapride at low concentrations (10(-9)M to 10(-8)M) enhanced electrical stimulation -evoked contraction and ACh release. The effect of cisapride was mimicked by methysergide and was not altered by ICS 205-930. Cisapride antagonized the 5-HT (5 X 10(-9) M)-induced inhibitory effect and the IC50 of cisapride was 1.5 X 10(-9) M. These findings indicate that enhancement by low concentrations of cisapride may be due to a block of the inhibitory 5-HT1 receptor. Cisapride at medium concentrations (10(-8) M to 3 X 10(-7) M) induced enhancement of electrical stimulation-evoked twitch contractions and ACh release evoked by electrical stimulation which were antagonized by 10(-6) M ICS 205-930, while this compound antagonized the 5-HT (2 X 10(-6) M)-and 2-methyl-5-HT-induced excitatory effects, and the IC50 of cisapride was 5.2 X 10(-8) M. Thus, cisapride acts on the putative 5-HT4 receptor as an agonist and the 5-HT3 receptor as an antagonist. Cisapride at high concentrations (10(-6) M to 10(-5) M) evoked contraction and the release of ACh, and these effects were antagonized by ICS 205-930 (10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cisapride stimulates motility of the intestine via the 5-hydroxytryptamine receptors. 189 Jun 14


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