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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several binding sites for serotonin or 5-hydroxytryptamine (5-HT) were identified by using selective agonists and antagonists. Today, 5-HT3 receptor types are considered to occupy a critical position in the emetic pathway. The discovery of 5-HT3 receptor antagonists originated from metoclopramide, an antidopaminergic drug introduced in France 25 years before as a modifier of digestive motricity; it represents a therapeutic advance, since it led to the first class of antiemetic drugs specifically designed to prevent severe cytotoxic drugs-evoked emesis and devoid of noticeable side-effects. It must be emphasized upon the necessity of developing new experimental tests in living animals and performing controlled trials on patients under chemotherapy to achieve this progress.
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PMID:[Value of 5-HT3 receptor antagonists, particularly as anti-emetic drugs]. 184 69

In the present experiments we have investigated the possible coupling of 5-hydroxytryptamine (HT)3 receptors to the metabolism of phosphatidylinositol (PI) in the rat fronto-cingulate and entorhinal cortices, two brain regions with relatively high density of this receptor subtype. 5-HT dose-dependently increases PI turnover (20-80% increase above basal stimulation), with an EC50 of 0.5 and 0.3 microM for fronto-cingulate and entorhinal cortices, respectively. This effect was blocked by the selective 5-HT3 antagonists, BRL 43694 (granisetron), GR 38032F (ondansetron) and ICS 205-930. The selective 5-HT3 receptor agonists, 2-methyl-serotonin (2-Me-5-HT) and phenylbiguanide (PBG), mimicked the action of 5-HT and dose-dependently produced a significant increase in PI turnover (46-76% of the 5-HT response). The stimulatory action of 2-Me-5-HT and phenylbiguanide was blocked completely by granisetron, ondansetron and ICS 205-930 but not by other receptor antagonists such as (+/-)-pindolol (a beta, 5-HT1A and 5-HT1B receptor antagonist), methy-sergide (a 5-HT1 and 5-HT2 receptor antagonist), ritanserin (a 5-HT1C and 5-HT2 receptor antagonist), SR 95103 (gamma-aminobutyric acidA receptor antagonist), scopolamine (a muscarinic antagonist), (-)-eticlopride (a D2 receptor antagonist), SCH 23390 (a D1 5-HT2/1C receptor antagonist) and prazosin (an alpha-1 receptor antagonist). In addition, the stimulation of PI turnover by 2-Me-5-HT was antagonized stereospecifically by the 5-HT3 receptor blocker zacopride. Thus, only the active enantiomer (S)-zacopride, but not the less active enantiomer (R)-zacopride, was effective in blocking the 2-Me-5-HT-induced effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of 5-hydroxytryptamine3 receptor agonists on phosphoinositides hydrolysis in the rat fronto-cingulate and entorhinal cortices. 184 25

1. The effects of various 5-hydroxytryptamine (5-HT) receptor agonists were examined following unilateral infusion into the substantia nigra (SN) of the guinea-pig. 2. The 5-HT1 receptor agonists, 5-carboxamidotryptamine (5-CT) (2-25 micrograms), sumatriptan (10-25 micrograms) and RU24969 (25 micrograms) all induced a marked contralateral rotation. In contrast, the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT, 10-25 micrograms) produced only a very small response, whilst the selective 5-HT1C/5-HT2 receptor agonist (+-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride ((+/-)-DOI) (25 micrograms) and the 5-HT3 receptor agonist, 2-methyl 5-HT (2-Me5-HT, 25 micrograms) were without effect. 3. The contralateral rotation induced by 5-CT (10 micrograms) was attenuated following pretreatment with the non-selective 5-HT1/5-HT2 receptor antagonists methiothepin (1 mg kg-1, s.c.) and metergoline (5-10 mg kg-1, s.c.) but not the 5-HT1C/5-HT2 antagonist ritanserin (1 mg kg-1, s.c.) or the 5-HT3 antagonist, ondansetron (0.5 mg kg-1, s.c.). An involvement of dopaminergic systems in the rotational response to 5-CT was implied by the antagonism of 5-CT-induced rotation by haloperidol (0.3 mg kg-1, s.c.). 4. At doses lower than those required to produce contralateral rotation, 5-CT (0.08-0.4 micrograms) and sumatriptan (2 micrograms) induced a small, but nonetheless consistent, ipsilateral rotation. 5. The data with agonists and antagonists taken together suggest that 5-CT-induced contralateral rotation may be mediated by 5-HTID receptor activation but definitive classification of the receptor will not be possible until selective 5-HTID-antagonists become available. This may therefore represent the first model to study this receptor subtype in vivo.
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PMID:Evidence that the unilateral activation of 5-HT1D receptors in the substantia nigra of the guinea-pig elicits contralateral rotation. 184 63

1. The effects of 5-hydroxytryptamine (5-HT) and of the 5-HT1-like receptor agonists, 5-carboxamidotryptamine (5-CT) and sumatriptan (GR43175) were investigated in isolated ring preparations of guinea-pig common iliac artery. 2. The three agonists induced very weak, if any, contractions of unstimulated preparations, whereas they elicited concentration-dependent contractions in preparations given a moderate tone by a threshold concentration of prostaglandin F2 alpha (PGF2 alpha). 3. Under the latter conditions, Emax values for 5-HT and 5-CT reached about 45% of PGF2 alpha maximal effect, whereas the Emax value of sumatriptan was significantly lower (about 35%). The rank order of potency (mean EC50 value, nM) was 5-CT (6.6) greater than 5-HT (22.9) greater than sumatriptan (155). Pargyline, cocaine or deoxycorticosterone were without significant effect on the contractions induced by 5-HT. 4. The 5-HT3 receptor antagonist, (1 alpha H, 3 alpha,5 alpha H-tropan-3-yl) 1-H-indole-3-carboxylic acid ester (ICS 205-930; 1 microM), had no effect on 5-HT-, 5-CT- and sumatriptan-induced contractions. 5. The 5-HT2 receptor antagonist, ketanserin (1 microM) caused only small rightward shifts (concentration-ratios, about 2) in the concentration-response curves to 5-HT, 5-CT and sumatriptan without significantly depressing the maximum effects. 6. In the presence of ketanserin (1 microM), the non-selective 5-HT receptor antagonist, methiothepin (0.1 microM), shifted the concentration-response curves to 5-HT and 5-CT to the right in a parallel manner and to a similar extent for both agonists (respective mean pKB values, 8.07 and 8.27). The effect of sumatriptan was also antagonized by methiothepin, but solvent effects precluded quantitative analysis of this antagonism. 7. It is concluded that 5-HT1-like receptors mediate the contractions induced by 5-HT, 5-CT and sumatriptan in guinea-pig isolated iliac artery. For reasons not yet understood, these receptors are detected only when the tissues are moderately pre-contracted by PGF2alpha.
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PMID:5-HT1-like receptors mediate 5-hydroxytryptamine-induced contraction of guinea-pig isolated iliac artery. 184 68

We have previously reported that serotonin (5-hydroxytryptamine [5HT]) alters cultured bovine pulmonary artery smooth muscle cell (SMC) configuration through two different regulatory mechanisms. We now report that 5HT also regulates SMC growth through these same two mechanisms--a stimulatory event initiated intracellularly and inhibition of growth resulting from a cell surface action. 5HT (1 microM) plus 0.1 mM iproniazid (a 5HT metabolic inhibitor) produced a severalfold stimulation of DNA synthesis (as measured by [3H]thymidine incorporation) of SMCs after a 17-24-hour incubation with only a slight elevation of cellular cAMP. This stimulatory effect responded synergistically with other growth factors including platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor and was effectively reversed by 5HT uptake inhibition. It was not produced by 5-hydroxyindoleacetic acid, a metabolite of 5HT. In the presence of 1 microM 5HT plus 0.1 mM isobutylmethylxanthine (IBMX), cAMP was elevated eightfold, dendritic formation occurred, and [3H]thymidine labeling of SMCs was inhibited. Inhibition of labeling by [3H]thymidine was mimicked by other agents that elevated cellular cAMP (10 microM histamine, 1 microM isoproterenol plus 0.1 mM IBMX, and 10 microM forskolin) and by 1 mM dibutyryl cAMP. This inhibitory effect was not blocked by either inhibition of 5HT uptake or 5HT-receptor antagonists ketanserin (5HT2); methiothepin, spiperone, and mianserin (5HT1/5HT2); and 3-tropanyl-indole-3-carboxylate and 3-tropanyl-3,5-dichlorobenzoate (5HT3). However, similar to 5HT, the 5HT1A agonist, (+/-)-8-hydroxy-(+/-)-2-dipropylamino-8-hydroxy-1,2,3, 4-tetrahydronaphthalenehydrobromide, in association with IBMX, produced an elevation in cAMP and inhibition of labeling by [3H]thymidine. 5HT, in the presence of either iproniazid or IBMX, did not alter [Ca2+]i, indicating that [Ca2+]i was not a signal for either of these actions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture. 185 Mar 32

Despite a number of significant advances over the past decade, prevention and treatment of chemotherapy-induced emesis remain formidable problems, particularly with cisplatin-containing regimens. Nearly one third of patients receiving high-dose cisplatin still experience substantial emesis despite the best available conventional antiemetics, and the toxic effects of these agents remain quite troublesome. In recent years, a new class of agents, the serotonin antagonists, has been identified. These agents hold promise for clinical utility in a wide range of areas. Selective antagonists of the serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor have proven in early clinical trials to be potent antiemetic agents in patients receiving cytotoxic chemotherapy, with efficacy comparable to or superior to that of conventional antiemetics. Toxic effects to date with the 5-HT3 receptor antagonists have been modest. The current state of knowledge with respect to these agents as antiemetics for patients receiving cytotoxic chemotherapy is summarized.
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PMID:Serotonin antagonists: a new class of antiemetic agents. 185 Aug 6

The potential of the investigational 5-hydroxytryptamine (5HT3) antagonist, LY277359, to alter cardiovascular, central nervous system (CNS), smooth muscle, and gastrointestinal functions at multiples of pharmacologically active doses, was examined to provide a profile of possible secondary pharmacological effects. In the anesthetized dog, significant cardiovascular effects were observed at doses 100-1000 and 4-15 times those found to be pharmacologically active at 5HT3 receptors in vivo in rats and dogs, respectively. These effects were limited to decreased heart rate (approximately 20%) at intravenous doses of 1.75 and 3.5 mg/kg and prolonged Q-Tc intervals (approximately 20 to 50%) at doses of 0.438 to 3.5 mg/kg. At an oral dose of 135 mg/kg (representing 1500-4500 times the pharmacologically active dose in rats), LY277359 induced hypoactive behavior and reduced body temperature in mice. Seizure activity was potentiated at high oral doses of LY277359 (45 and 135 mg/kg). A single oral dose of 135 mg/kg increased hexobarbital-induced sleep time. In smooth and cardiac muscle tissue studies in vitro, LY277359 was essentially inactive: it did not alter contractile activity or receptor function of the guinea pig ileum, rat vas deferens, rat uterus, or guinea pig atria at concentrations of 10(-5) to 10(-10) mol/l. At a concentration 50,000 times the 5HT3 antagonistic level in vitro (10(-4) mol/l), LY277359 inhibited the response of the ileum to field stimulation, acetylcholine and angiotensin I, and suppressed the rate of the spontaneously beating guinea pig atria in a noncompetitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:General pharmacology of a new potent 5-hydroxytryptamine antagonist. 186 53

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

1. The effects of 5-hydroxytryptamine (5-HT) on the release of cholexystokinin-like immunoreactivity (CCK-LI) were examined in synaptosomes prepared from rat cerebral cortex and nucleus accumbens and depolarized by superfusion with 15 mM KCl. 2. In both areas 5-HT, tested between 0.1 and 100 nM, increased the calcium-dependent, depolarization-evoked CCK-LI release in a concentration-related manner. The concentration-response curves did not differ significantly between the two brain areas (EC50: 0.4 +/- 0.045 nM and 0.48 +/- 0.053 nM, respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 nM 5-HT). 3. The 5-HT1/5-HT2 receptor antagonist methiothepin (300 nM) did not affect the CCK-LI release elicited by 10 nM 5-HT. However, the effects of 10 nM 5-HT were antagonized in a concentration-dependent manner by the 5-HT3 receptor antagonists (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930; 0.1-100 nM; IC50: 3.56 +/- 0.42 nM in the cortex and 3.90 +/- 0.50 nM in the n. accumbens) and ondasetron (IC50: 8.15 +/- 0.73 nM in the cerebral cortex). 5-HT (10 nM) was also strongly antagonized by 100 nM 1 alpha H, 3 alpha 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) another blocker of the 5-HT3 receptor. Moreover, the 5-HT3 receptor agonist 1-phenylbiguanide (tested in the cerebral cortex between 0.1 and 100 nM) enhanced CCK-LI release in a manner almost identical to that of 5-HT (EC50 = 0.64 +/- 0.071 nM). 4. It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs.
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PMID:Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens. 193 41

Two subtypes of excitatory 5-hydroxytryptamine (5-HT) receptor, 5-HT1P and 5-HT3, are found on type 2-AH neurons of the guinea pig myenteric plexus. The 5-HT1P receptor mediates a slow and the 5-HT3 receptor a fast depolarization of these cells, however, the role of these receptors in the physiology of the gut is unknown. Renzapride (BRL 24924), a substituted benzamide, has previously been found to antagonize responses of myenteric neurons mediated by both 5-HT1P and 5-HT3 receptors. The effects on myenteric type 2-AH neurons of a structurally similar benzamide, zacopride, which unlike renzapride has S and R stereoisomers, were investigated to gain further insight into 5-HT receptor function. In contrast to renzapride, S-, but not R-zacopride, was found to mimic the 5-HT1P receptor-mediated slow response to 5-HT. Desensitization of 5-HT1P receptors with 5-HT inhibited slow depolarizing responses to S-zacopride, and desensitization with S-zacopride antagonized slow responses to 5-HT. Responses to S-zacopride were also inhibited by renzapride and the 5-HT1P receptor antagonist N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP). S-zacopride, like renzapride and 5-HT, presynaptically inhibited nicotinic fast excitatory postsynaptic potentials, an effect that can be mediated by 5-HT1P or 5-HT1A receptors. Both S and R stereoisomers of zacopride antagonized 5-HT3 receptor-mediated fast responses to 5-HT. Unlike 5-HTP-DP, neither zacopride or its stereoisomers nor renzapride inhibited the binding of 5-[3H]HT to 5-HT1P receptors. [3H]zacopride (5-10 nM) was found to bind to a site in the gut from which it could be displaced by a 1,000-fold excess of renzapride and S-zacopride (but not R-zacopride) greater than 5-HTP-DP much greater than the 5-HT3 receptor antagonist ICS 205-930. These observations suggest that, in addition to 5-HT3 receptors, there is a benzamide binding site on myenteric neurons that interacts with, but is distinct from, the 5-HT recognition site of 5-HT1P receptors. Benzamides may affect coupling of the 5-HT1P receptor to its effector.
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PMID:Use of stereoisomers of zacopride to analyze actions of 5-hydroxytryptamine on enteric neurons. 198 11


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