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

The effect of six 5-HT3 receptor antagonists: ondansetron (0.01-3 mg/kg ip), granisetron (0.01-1 mg/kg ip), zacopride (0.01-3 mg/kg ip), tropisetron (0.001-0.1 mg/kg ip), MDL 72222 (0.01-3 mg/kg ip) and DAU 6215 (0.01-3 mg/kg sc) were examined in the conflict drinking test (Vogel test) and in the elevated plus-maze test in rats. Ondansetron (0.1-0.3 or 1 mg/kg), zacopride (0.1-1 mg/kg) and tropisetron (0.01 mg/kg) increased the punished responding in the Vogel test and showed anxiolytic effects in the elevated plus-maze test. Their effects were limited to a narrow dose range and were not dose-dependent. Granisetron (0.1 mg/kg) exhibited an anti-conflict activity, but was ineffective in the elevated plus-maze test. MDL 72222 and DAU 6215 were ineffective in both those tests. On the other hand, diazepam (2.5-10 mg/kg), used as a reference drug, was active in either procedure and its effects were dose-dependent. These results indicate that an anxiolytic-like activity is not a common characteristic of 5-HT3 receptor antagonists. Moreover, even the anxiolytic action of drugs which were active in the experimental models used should be accepted with caution.
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PMID:The anxiolytic-like effects of 5-hydroxytryptamine3 (5-HT3) receptor antagonists. 147 May 64

(+)SKF 10,047 preferentially increased dopamine release in the nucleus accumbens compared to the striatum. Dopamine output was evaluated in the same freely moving rats by trans-cerebral dialysis. Clozapine and DAU 6215, a 5HT3 antagonist, which itself did not modify dopamine release in both areas, selectively antagonized (+)SKF 10,047-induced dopamine release in the nucleus accumbens. Haloperidol by itself increased dopamine release in both areas and these effects were additive with those induced by (+)SKF 10,047.
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PMID:Effect of haloperidol and clozapine on (+)SKF 10,047-induced dopamine release: role of 5-HT3 receptors. 149 54

The cardiovascular effects of DAU 6215, a novel 5-HT3 receptor antagonist were studied. DAU 6215 (20 micrograms/kg) inhibited the serotonin-induced Bezold-Jarisch reflex in anaesthetized rats, but did not affect the mean blood pressure and heart rate in anaesthetized rats, in anaesthetized animals after bilateral vagotomy and in pithed rats. This substance also did not affect the serotonin-induced rise in blood pressure in pithed rats and did not influence the response of the isolated rat tail artery to 5-HT. Moreover, DAU 6215 did not change the cardiovascular effects of noradrenaline- and angiotensin-II-stimulated constriction of rat tail artery. Our data suggest that DAU 6215 is rather a selective antagonist, without an affinity to 5-HT2, alpha-adrenoceptors, beta-adrenoceptors and angiotensin II receptors.
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PMID:Influence of DAU 6215, a novel 5-HT3 receptor antagonist, on the cardiovascular system in anaesthetized and pithed rats. 152 6

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

Electrophysiological techniques were used to study the effects of the new compound, DAU 6215 ((3-alpha-tropanyl) 1H-benzimidazolone-3-carboxamide chloride), a selective 5-HT3 receptor antagonist, on the activity of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Acute i.v. injections of DAU 6215 did not cause any change in the basal firing rate of DA neurons in the SNc or in the VTA. Pretreatment with DAU 6215 did not modify the inhibitory effect of apomorphine on the firing rate of midbrain DA neurons. Acute s.c. administration of DAU 6215 caused a significant increase in the number of spontaneously active DA neurons in the VTA but not in the SNc. This effect was similar to that of acute clozapine, whereas acute haloperidol caused a significant increase of spontaneously active DA neurons in both the SNc and the VTA. Repeated consecutive s.c. administration of DAU 6215 and clozapine for 21 days produced a significant decrease in the number of spontaneously active DA neurons in the VTA but not in the SNc. Chronic haloperidol (21 days) decreased the number of DA cells both in the SNc and VTA. The effect of chronic DAU 6215 on the activity of VTA DA neurons was reversed by apomorphine, suggesting that these neurons were probably under a state of depolarization block. These findings indicate that DAU 6215 may have potential antipsychotic activity, probably associated with a low incidence of extrapyramidal side-effects.
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PMID:Chronic treatment with DAU 6215, a new 5-HT3 receptor antagonist, causes a selective decrease in the number of spontaneously active dopaminergic neurons in the rat ventral tegmental area. 158 49

A putative 5-HT4 receptor-mediated depolarization of the rat isolated vagus nerve has been studied using a grease-gap extracellular recording technique. Ondansetron (1 microM) was used to block the predominant 5-HT3 receptor mediated depolarization in this preparation and the effects of the 5-HT4 receptor antagonists DAU 6285 (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl-2,3-dihydro-6-methoxy-2-oxo-1H-benzimidazole-1- carboxylate HCl); 0.3, 1.0 or 3.0 microM and SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)-ethyl ester HCl); 0.1, 0.3 or 1.0 microM were studied on the residual, ondansetron-resistant, component of the response. The effects of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) and of forskolin on the ondansetron-resistant response were also studied. Both DAU 6285 and SDZ 205-557 acted as competitive antagonists of the ondansetron-resistant response to 5-HT with pA2 values of 6.8 (6.7-7.1, n = 12) and 7.1 (6.9-7.5, n = 12) respectively. The vagus nerve was depolarized by IBMX (100 microM) or forskolin (10 microM), the effects being similar to the maximum response to 5-HT. In the presence of IBMX (100 microM) or forskolin (10 microM) the ondansetron-resistant component of the response to 5-HT was enhanced and the 5-HT3 receptor-mediated component reduced. These results with DAU 6285 and SDZ 205-557 are consistent with a 5-HT4 receptor-mediated mechanism of the ondansetron-resistant depolarizing response to 5-HT.
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PMID:Further characterization of the putative 5-HT4 receptor mediating depolarization of the rat isolated vagus nerve. 747 28

The role of endogenous serotinin in the formation of gastric damage was studied in rats. Stress ulcers were induced by ultrasounds, immobilization and immobilization plus cold. The damage of gastric mucosa was estimated (arbitrary scale) and serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in this tissue measured. In all examined groups of animals with gastric mucosal damages the lower levels of 5-HT and 5-HIAA in gastric mucosa were observed. In some experimental groups animals were treated with serotonergic receptor antagonists 30 min. before stress. The administration of ICS 205-930 (80 micrograms/kg), 5-HT3 receptor antagonist, and DAU-62855 (80 micrograms/kg), 5-HT4/5-HT3 receptors antagonist, reduced the intensity of stress gastric injuries. In contrast the administration of methysergide (8 mg/kg), 5-HT1/5-HT2 receptors antagonist, enhanced the stress gastric mucosa damage. 16, 16 dimethyl PGE2 (10 micrograms/kg) protected stomach against stress stimuli and accompanied increase of serotonin and 5-HIAA concentration in gastric mucosa was observed. Both 5-HT3/5-HT4 receptor antagonist had an additive cytoprotective effect when given in combination with PGE2 analog. In the presence of methysergide gastroprotective effect of PGE2 was abolished. The present studies demonstrate that cytoprotective effect of endogenous serotonin depends on 5-HT1 and 5-HT2 receptors stimulation in the gastric mucosa and the protective effect of prostaglandins depends partly on the regulation of serotonin metabolism.
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PMID:Gastric cytoprotective activity of endogenous 5-HT. 753 26

5-HT-induced acute gastric mucosal injury was assessed in rats by using 5HT1, 5HT2, 5HT3, 5HT4 or muscarinic receptor related drugs. Rats were treated with antagonists i.p. and 30 minutes later either vehicle, 5-HT (20 mg/kg) or other agonists were administered s.c. The stomachs were removed 4 hours after the last injection and mucosal integrity was assessed by light microscopy using a histological ulcer index (HUI). The HUI was found to be significantly increased following 5-HT administration (1.57 +/- 0.3) when compared with controls (0.14 +/- 0.1). 5HT1 agonist 5-carboxamidotryptamine (20 mg/kg) produced acute gastric erosion and increased the HUI (P < 0.05). The HUI in the animals receiving 5-HT1D agonist sumatriptan (7 mg/kg) was found to be 1.62 +/- 0.24. 5HT2 antagonist ketanserine (2.5-15 mg/kg), 5HT3 antagonist ondansetron (1-5 mg/kg), 5HT4 antagonist DAU 6285 (1-10 mg/kg) and atropine (1.5-30 mg/kg) exerted no effect whereas 5HT1/2 antagonist metitepine (0.05-0.5 mg/kg) caused a dose dependent inhibition of the effect of 5-HT. The results from this study demonstrate that 5-HT causes acute gastric mucosal injury and this injury is probably due to the activation of the 5-HT1D receptors.
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PMID:Serotonin causes acute gastric mucosal injury in rats, probably via 5HT1D receptors. 754 36


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