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 paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((+-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dih yd ro- 2H-1,4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 receptors at the synaptic membranes of the rat cerebral cortex with a Ki value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 microM) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, alpha 1-adrenoceptor, alpha 2-adrenoceptor, muscarine and benzodiazepine) even at a 10 microM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.
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PMID:Antagonistic activity of Y-25130 on 5-HT3 receptors. 133 90

The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure. Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibit both dopamine D2- and 5-HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that contribute to their effectiveness. The cannabinoids are effective in cytotoxic-induced vomiting, perhaps acting via endorphin receptors or by inhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral neuronal 5-HT3 receptors. Vomiting constitutes a major disadvantage to the use of many drugs; vomiting induced by aminoglycoside antibiotics appears to be due to ototoxicity and is relieved by histamine H1-receptor antagonists. The protracted vomiting associated with the use of some cytotoxics in cancer chemotherapy may involve psychic components, the chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, such as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved would appear to offer improved control. The use of dopamine receptor antagonists in controlling emesis induced by dopamine agonists used in Parkinson's disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drugs may produce some impairment of therapeutic responses to the agonists. Muscarinic and nicotinic agonists currently under investigation in Alzheimer's disease pose another therapeutic dilemma as emesis is due to a central action of these compounds. Several sites may be involved including the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or mu-receptors on dopaminergic nerves, but serotonergic mechanisms may also be involved in the action of some opiates.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacological agents affecting emesis. A review (Part I). 137 16

Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs. 207 88

Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist. Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dopamine receptor antagonist properties. Subsequent alteration of the aromatic nucleus led to the identification of indazoles 6a-h, and 1- and 3-indolizines 7b-d and 8, and imidazo[1,5-alpha]pyridines 9 and 10, as potent 5-HT3 receptor antagonists devoid of either dopamine antagonist or gastric motility stimulatory properties. Further conformational restriction of the side chain identified quinuclidine 11 and isoquinuclidine 12 as potent 5-HT3 receptor antagonists which mimic the distorted chair conformation of the tropane with, in the case of 11, the N-methyl group axial. From these series, 6g (BRL 43694) was found to be both potent and selective and has been shown to be a very effective antiemetic agent against cytotoxic drug induced emesis both in the ferret and in man.
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PMID:5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives. 236 70

5-HT3 receptor antagonists may have both antiemetic and gastric and intestinal motility stimulating properties, but they differ in their relative potencies and efficacies for these two activities. Since the 5-HT3 receptor is present on enteric neurons, intracellular recordings of myenteric neuronal transmembrane potential were used to assess the actions of four proposed motility stimulating drugs, metoclopramide, BRL 24924, ICS 205-930 and cisapride. BRL 24924 (10(-6) M), ICS 205-930 (10(-7) M) and cisapride (5 x 10(-6) M) each antagonized the 5-HT3-mediated fast depolarization of myenteric neurons. Metoclopramide (10(-5) M) was less consistent in its ability to antagonize this response, and the response often returned in the continued presence of metoclopramide. In the present study, BRL 24924 (10(-6) M) and, as previously shown, cisapride (5 x 10(-6) M) antagonized the slow depolarization of myenteric neurons induced by 5-HT. Metoclopramide (10(-5) M), BRL 24924 (10(-6) M) and cisapride (5 x 10(-6) M), but not ICS 205-930 (10(-7) M) depolarized myenteric neurons within the first 2 min of contact with myenteric neurons. These data support the view that there are separate receptors that may be responsible for the prokinetic actions of these drugs and a series of 5-HT3-mediated actions which include antiemesis.
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PMID:Gastrointestinal motility stimulating drugs and 5-HT receptors on myenteric neurons. 280 67

Metoclopramide is a stimulant of upper gut motility and an anti-emetic. The mechanisms by which the drug exerts these actions has been the subject of considerable research, which is briefly reviewed in this article. From the viewpoint of drug discovery, the properties of metoclopramide have directly led to the development of selective gut motility stimulants and 5-HT3 receptor antagonists. These events and the potential clinical use of such compounds are reviewed in detail.
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PMID:From metoclopramide to selective gut motility stimulants and 5-HT3 receptor antagonists. 307 95

The involvement of 5-hydroxytryptamine (5-HT) 5-HT3 receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT3 receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT3 receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT3 receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.
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PMID:Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis. 331 Nov 9

1. The binding characteristics of [3H]ICS 205-930, a potent and selective 5-hydroxytryptamine 5-HT3 receptor antagonist, were investigated in membranes prepared from murine neuroblastoma-glioma NG 108-15 cells. 2. [3H]ICS 205-930 bound rapidly, reversibly and stereoselectively to a homogeneous population of high affinity recognition sites: Bmax = 58 +/- 3 fmol/mg protein, pKD = 9.01 +/- 0.08 (n = 11). Non linear regression and Scatchard analysis of saturation data suggested the existence of a single class of [3H]ICS 205-930 recognition sites on NG 108-15 cells. The binding was rapid, stable and reversible. The affinity of [3H]ICS 205-930 determined in kinetic studies was in agreement with that obtained under equilibrium conditions. 3. Competition studies performed with a variety of agonists and antagonists also suggested the presence of a homogeneous population of [3H]ICS 205-930 recognition sites. All competition curves were steep and monophasic and were best fit by a 1 receptor site model. [3H]ICS 205-930 binding sites displayed the pharmacological profile of a 5-HT3 receptor. Potent 5-HT3 receptor antagonists showed nanomolar affinities for [3H]ICS 205-930 binding sites with the following rank order of potency: SDZ 206-830 greater than ICS 205-930 greater than SDZ 206-792 greater than BRL 43694 greater than quipazine greater than BRL 24924 greater than SDZ 210-204 greater than MDL 72222 greater than SDZ 210-205. Metoclopramide, mCP and mianserin showed submicromolar affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterisation of 5-HT3 recognition sites in membranes of NG 108-15 neuroblastoma-glioma cells with [3H]ICS 205-930. 341 89

The effects of 5-hydroxytryptamine (5-HT) on an inward current activated by extracellular ATP were investigated in rat pheochromocytoma PC12 cells. Under whole-cell voltage-clamp conditions 5-HT (10 microM) reversibly enhanced the amplitude of the current activated by 30 microM ATP. The enhancement may not be due to an increase in the number of functional channels because the current activated by 300 microM ATP was not remarkably augmented compared with the current activated by 30 microM ATP. The current enhancement by 100 microM 5-HT was less obvious than that by 10 microM 5-HT. When the current kinetics were compared, activation of the ATP-evoked current was accelerated to the same extent by either 10 or 100 microM 5-HT, whereas deactivation was largely more accelerated by 100 microM 5-HT. Propranolol (10 microM), a 5-HT1 receptor antagonist, or LY53857 (10 microM), a 5-HT2 receptor antagonist, exerted an agonistic effect: the ATP-activated current was facilitated by these compounds. Metoclopramide (10 microM), a 5-HT3 receptor antagonist, neither facilitated the ATP-activated current, nor blocked the current facilitation by 5-HT. Guanosine 5'-O-(2-thiodiphosphate) (GDP[beta S]) (2 mM), the non-hydrolysable analog of guanosine 5'-triphosphate (GTP), or K-252a (2 microM), a protein kinase inhibitor, did not affect the facilitation by 5-HT of the ATP-activated current when they were included in the intracellular solution. The ATP-activated current pre-facilitated by 10 microM dopamine was not enhanced by 10 microM 5-HT. Similarly, the pre-facilitation by 5-HT attenuated the current enhancement by dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Facilitation by 5-hydroxytryptamine of ATP-activated current in rat pheochromocytoma cells. 752 34

1. Noxious colo-rectal distension was applied in conscious rats by acute balloon inflation and the effects observed as abdominal muscle contraction with the threshold typically between 10-40 mmHg. The effects of 5-HT3 receptor antagonists on responses to noxious colo-rectal distension were then studied in both normal rats and those pretreated with 5-hydroxytryptophan (5-HTP). 2. Granisetron and ondansetron (10 micrograms kg-1 and 1 mg kg-1, s.c.) had no effect on visceromotor thresholds to colo-rectal distension in normal rats. 3. Hypersensitivity of the colo-rectum was achieved by systemic administration of a low dose of 5-HTP (10 mg kg-1, s.c.) which lowered the distension pressure required to induce the visceromotor reflex; analysis of variance showed a highly significant treatment effect (F1,11 = 84.26, P < 0.001). 4. Granisetron, zatosetron, bemesetron and renzapride equi-potently increased the threshold values at which distension evoked a visceromotor reflex after dosing with 5-HTP, with a maximal response 3.6 to 4.2 fold above saline controls, at 10 micrograms kg-1, s.c. Metoclopramide (10 micrograms kg-1) also raised the level of distension required to elicit a response. By comparison, tropisetron caused a small, non-significant increase in visceromotor threshold values and only at high doses (1 mg kg-1), whilst ondansetron and BRL 46470 had no significant effects at doses up to 10 mg kg-1. 5. The response to granisetron (10 micrograms kg-1, s.c.) in 5-HTP-treated rats was unaltered by pre-administration of naloxone (5 mg kg-1, s.c.). 6. These results suggest that a 5-HT3-like receptor modulates 5-HTP- evoked visceral hypersensitivity.However, the rank order of antagonist potency does not correlate with their order of potency against the classically defined 5-HT3 receptor.
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PMID:Differences between 5-HT3 receptor antagonists in modulation of visceral hypersensitivity. 788 56


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