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 pharmacological characterisation and topographical distribution of [3H]-(S)-zacopride recognition sites in the forebrain of the rat was studied using homogenate and autoradiographic radioligand binding techniques. [3H]-(S)-Zacopride labelled a single, saturable, specific binding site (defined by 10.0 microM granisetron) in homogenates prepared from the entorhinal cortex of the rat (pKD = 9.51 +/- 0.08; Bmax = 104 +/- 7 fmol mg-1 protein; mean +/- SEM, n = 8). Pharmacological characterisation of the recognition site, within the entorhinal cortex, suggested that [3H]-(S)-zacopride selectively labelled the recognition site of the 5-HT3 receptor. Specific binding of [3H]-(S)-zacopride (defined by 1.0 microM granisetron) was differentially distributed throughout the forebrain of the rat; highest densities were located within sub-nuclei of the amygdala (cortical amygdaloid nucleus, amygdalohippocampal area, posterior medial cortical amygdaloid nucleus, posterior lateral amygdaloid nucleus), cortical areas (primary olfactory cortex, entorhinal cortex) and hippocampus. Non-specific binding was distributed homogeneously, although lower in myelinated structures. It is concluded that [3H]-(S)-zacopride selectively labels 5-HT3 receptor recognition sites within the forebrain of the rat; the topographical distribution of these sites, within the limbic nuclei, is consistent with the behavioural actions in animal models of the selective 5-HT3 receptor antagonists.
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PMID:Characterisation and autoradiographic localisation of 5-HT3 receptor recognition sites identified with [3H]-(S)-zacopride in the forebrain of the rat. 208 55

The role of 5-HT3 receptors in the biphasic vasodilator response to serotonin (5-hydroxytryptamine; 5-HT) was investigated in the forearm of 7 young healthy volunteers (aged 22-32 years). Single dose infusions of 5-HT (1 ng/kg/min) and of acetylcholine (ACh, 500 ng/kg/min) were administered into the brachial artery. Subsequently combined infusions of 5-HT together with the selective 5-HT3 receptor antagonist ICS 205-930 (350 and 700 ng/kg/min), and ACh together with ICS 205-930 (700 ng/kg/min) were given. After a pause of at least 1 hour the single infusions of 5-HT and ACh were repeated. Subsequently, 5-HT and ACh were infused together with atropine (100 ng/kg/min). Forearm blood flow (FBF) was measured by R-wave triggered venous occlusion plethysmography. Heart rate (HR) and i.a. blood pressure (BP) were recorded semi-continuously. None of the drugs in the doses used did induce systemic hemodynamic effects. After an initial rapid transient increase in FBF of 316 +/- 55%, 5-HT elicited a persistent increase in FBF of 90 +/- 22% (mean +/- SEM, p less than 0.05 for both). ACh induced a monophasic vasodilatation of 475 +/- 123% (p less than 0.05). Both the initial transient and the persistent dilatator response to 5-HT were attenuated by ICS 205-930 350 ng/kg/min (p = 0.057, n = 5) and 700 ng/kg/min (p less than 0.05, n = 7). The highest dose of ICS 205-930 did not significantly influence the dilatator response to ACh. Atropine abolished the ACh induced vasodilatation (p less than 0.05), but did not influence the biphasic dilatator response to 5-HT. Thus the 5-HT induced biphasic vasodilatation was antagonized by ICS 205-930, indicating that this response was mediated by 5-HT3 receptor activation. The fact that atropine did not influence the vascular response to 5-HT suggests that 5-HT did not induce vascular relaxation indirectly by the release of ACh from cholinergic nerve endings.
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PMID:Serotonin induced vasodilatation in the human forearm is antagonized by the selective 5-HT3 receptor antagonist ICS 205-930. 318 2

The affinities of a range of structurally diverse 5-HT3 receptor agonists and antagonists for [3H]-granisetron binding sites have been measured in membrane homogenates prepared from central and peripheral tissues of the mouse. By comparing the affinities of compounds across these tissues, the question of whether intra-species 5-HT3 receptor subtypes exist in the mouse has been addressed. In entorhinal cortex and brainstem, [3H]-granisetron bound to a single high affinity saturable binding site (Kd 0.47 +/- 0.14 and 0.60 +/- 0.05 nM; Bmax 20 +/- 6 and 7 +/- 2 fmol (mg protein)-1 respectively; mean +/- SEM; n = 3). In distal and proximal colon, the specific binding of [3H]-granisetron was best fitted to a 2-site model. Kd values obtained for the high affinity site were similar to those obtained in brain tissue (distal colon: 0.47 +/- 0.09 nM, n = 4; proximal colon: 0.39 +/- 0.09 nM, n = 4). In salivary gland, 2-sites were evident in 2 out of 4 experiments. The Kd value (calculated from the high affinity site in the 2-site model) was approximately 10-fold less than in brain or colon (3.3 +/- 1.1 nM, n = 4). Bmax values were 7 +/- 2, 4 +/- 1 and 71 +/- 16 fmol (mg protein)-1 for distal colon, proximal colon and salivary gland respectively. For all tissues the estimated affinity of the low affinity site was variable, and Bmax values could not be reliably calculated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A pharmacological comparison of [3H]-granisetron binding sites in brain and peripheral tissues of the mouse. 760 74

The novel 5-HT3 antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT3 receptor antagonism, BRL 46470A was shown to antagonise 5-HT3 mediated responses in the guinea-pig ileum [pA2 8.3 +/- 0.5, slope 0.98 +/- 0.20, mean +/- SEM (5)], the rabbit isolated heart (pA2 10.1 +/- 0.1, slope 1.2 +/- 0.2, n = 5) and the rat Bezold-Jarisch model (ID50 0.7 microgram/kg IV +/- 0.1, n = 8), with a long duration of action (> 3 h). BRL 46470A selectively displaced [3H]-BRL 43694 from 5-HT3 binding sites in rat brain membranes (Ki 0.32 nM +/- 0.04, n = 4) without displacing (at concentrations greater than 1 microM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects-elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001-0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT3 receptor antagonist ondansetron, with no evidence of a bell-shaped dose response curve over 4 orders of magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties. 783 18

Using N1E-115 neuroblastoma cells as an experimental model, we have examined if four commonly used i.v. anaesthetic induction agents interact with 5-HT3 receptors. Specifically, we tested the hypothesis that the antiemetic effects of propofol may result from 5-HT3 receptor antagonism. Binding of tropisetron (a 5-HT3 selective reference compound), etomidate, ketamine, thiopentone and propofol to 5-HT3 receptors was assessed by measuring the displacement of [3H]BRL 43694 from whole N1E-115 cells. The rank order potency (Ki) was tropisetron (1.7 (SEM 0.2) nmol litre-1) >> etomidate (83.(4) mumol litre-1) > or = ketamine (97 (4) mumol litre-1) > thiopentone (177 (9) mumol litre-1) > propofol (819 (171) mumol litre-1). With the exception of thiopentone these effects were outside the clinical range and suggest that anaesthetic agents are unlikely to interact directly with 5-HT3 receptors, and that other mechanism(s) must underlie the antiemetic effects of propofol.
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PMID:Interaction of i.v. anaesthetic agents with 5-HT3 receptors. 877 9

Autoradiographic binding studies using the 5-HT3 (5-hydroxytryptamine3) receptor radioligand, [3H]-(S)-zacopride (0.5 nM), identified a heterogeneous distribution of specific binding sites (defined by granisetron, 1 microM) throughout the human brain. Highest radiolabelled 5-HT3 receptor densities were detected in discrete nuclei within the brainstem (nucleus tractus solitarius, area postrema, spinal trigeminal nerve nucleus; 50-200 fmol/mg tissue equivalent) with more modest levels of expression in the forebrain (e.g. hippocampus, nucleus accumbens, putamen, caudate; 4-17 fmol/mg tissue equivalent). Within the hippocampal formation, radiolabelled 5-HT3 receptors were differentially distributed with highest levels in the granule cell layer of the dentate gyrus. Saturation studies with [3H]-(S)-zacopride (0.05-16 nM; non-specific binding defined by granisetron, 10 microM) binding to homogenates of human putamen indicated that [3H]-(S)-zacopride (0.05-16 nM; non-specific binding defined by granisetron, 10 microM) binding to homogenates of human putamen indicated that [3H]-(S)-zacopride labelled an apparently homogenous population of binding sites (Bmax = 72 + 7 fmol mg-1 protein, pKd = 8.69 +/- 0.09, Hill coefficient = 0.99 +/- 0.06, mean +/- SEM, n = 4). The pharmacological profile of [3H]-(S)-zacopride binding to homogenates of putamen indicated the selective labelling of the human variant of the 5-HT3 receptor. The marked differences, however, in the pharmacology (e.g. low affinity for D-tubocurarine) and relative distribution (e.g. presence of 5-HT3 receptors in the human extrapyramidal system) of 5-HT3 receptors in the human forebrain when compared with other species further necessitates caution in predicting clinical responses based on data generated in animal models of disease.
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PMID:Autoradiographic distribution of [3H]-(S)-zacopride-labelled 5-HT3 receptors in human brain. 899 13

The 5-HT3 receptor is a ligand-gated ion channel with significant structural similarity to the nicotinic acetylcholine receptor. Several regions that form the ligand binding site in the nicotinic acetylcholine receptor are partially conserved in the 5-HT3 receptor, presumably reflecting the conserved signal transduction mechanism. Specific amino acid differences in these regions may account for their distinct ligand recognition properties. Using site-directed mutagenesis, we have replaced one of these residues, glutamate 106 (E106), with aspartate (D), asparagine (N), alanine (A) or glutamine (Q) and characterized the ligand-binding and electrophysiological properties of the mutant receptors after transient expression in HEK-293 cells. The affinity for the selective 5-HT3 receptor antagonist [3H]GR65630 was decreased 14-fold in the mutant E106D (Kd = 3.69 +/- 0.32 nM) when compared to wildtype (WT, E106) 5-HT3 receptor (0.27 +/- 0.03 nM), while the affinity for E106N was unchanged (0.42 +/- 0.07 nM, means +/- SEM, n = 3-10). Decreased affinities for both E106D and E106N were observed for the antagonists granisetron, ondansetron and renzapride and for the agonists 5-HT (130- and 30-fold) and 2-methyl-5-HT (250- and 20-fold), respectively. Both mutants still formed 5-HT-activatable ion channels, but the high Hill coefficient of the concentration effect curves in wildtype (2.0) was decreased to unity in both cases. The EC50 of 5-HT was increased seven-fold in E106N (8.7 microM) when compared to wildtype (1.2 microM), but unchanged in E106D, and the potency of the antagonist ondansetron for both mutants was decreased. E106A and E106Q expressed poorly preventing a detailed characterization. These data suggest that E106 contributes to the ligand-binding site of the 5-HT3 receptor and may form an ionic or hydrogen bond interaction with the primary ammonium group of 5-HT.
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PMID:Analysis of the ligand binding site of the 5-HT3 receptor using site directed mutagenesis: importance of glutamate 106. 922 89

We investigated whether radiation-induced pica, a behavior characterized by the eating of a non-food substance, such as kaolin, can be used as an index of radiation-induced vomiting in rats. Since there was an individual difference in the susceptibility to pica, we selected rats that actually ate kaolin following X-ray irradiation, and used them for the experiment. The total-body irradiation (TBI) increased kaolin consumption in a dose-dependent manner (sham, 0.05 +/- 0.03 (SEM) g; 2 Gy, 0.38 +/- 0.11 g; 4 Gy, 1.54 +/- 0.28 g; 8 Gy, 3.55 +/- 0.67 g), and the increased kaolin consumption after 4 Gy of TBI was inhibited by a pretreatment with the serotonin 5-HT3 receptor antagonist ondansetron (2 mg/kg, i.p.) (saline, 1.49 +/- 0.33 g; ondansetron, 0.75 +/- 0.11 g). Furthermore, 4 Gy of abdominal irradiation was more effective to induce pica than that of head irradiation (abdomen: 0.37 +/- 0.05 g, head: 0.06 +/- 0.01 g). These findings suggested that peripheral serotonergic pathway is predominantly involved in the development of radiation-induced pica in rats and that the radiation-induced pica could be useful as a behavioral index for the severity of radiation-induced vomiting in rats.
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PMID:Establishment of an animal model for radiation-induced vomiting in rats using pica. 1223 27