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)

In rat pheochromocytoma (PC12) cells, nerve growth factor (7S NGF) induced the expression of recognition sites that bind the specific 5-HT3 antagonist (S-) [3H]zacopride. Culturing PC12 cells for 8-12 days in the presence of 50 ng/ml NGF increased the density (Bmax) of (S-) [3H]zacopride binding sites in cell membranes (0-100,000 x g fraction) from 0 to 105 fmoles/mg protein. This binding exhibited high affinity for (S-) [3H]zacopride (Kd = 0.8 nM), was specific (greater than 95%), and was inhibited by 5-HT3 compounds with a rank of potency (quipazine greater than ICS 205-930 greater than GR38032F greater than BRL24924 approximately MDL 72222 greater than phenylbiguanide greater than or equal to serotonin greater than 2-methyl-serotonin greater than metoclopramide) which was distinct from neuroblastoma cells. Thus, NGF-differentiated PC12 cells possess a 5-HT3 receptor and should be useful to investigate its regulation and biochemical mechanism of action.
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PMID:Nerve growth factor induces 5-HT3 recognition sites in rat pheochromocytoma (PC12) cells. 234 88

A 5-hydroxytryptamine 5-HT3 receptor binding site has been purified from deoxycholate-solubilized NCB20 cell membranes. Purification (1,700-fold) was achieved in one step by affinity chromatography with L-685,603 immobilized on agarose. The 5-HT3 selective antagonist [3H]Q ICS 205-930 labeled a single population of receptors in the affinity-purified preparation with a Bmax of 3.1 +/- 0.9 nmol/mg protein and Kd of 0.40 +/- 0.05 nM (mean +/- S.E., n = 3). The rank order of potency for a series of competing compounds confirmed that [3H]Q ICS 205,930 was labeling a 5-HT3 receptor in the purified preparation, and the inhibition constants for all antagonists were unchanged after purification. The purified 5-HT3 binding site eluted from a Sepharose 6B gel filtration column in a similar manner to the crude solubilized preparation (Stokes radius of 4.9 nm, apparent molecular size 250,000). Polyacrylamide gel electrophoresis of the affinity-purified receptor showed two broad bands by silver staining, migrating with apparent molecular masses of 54,000 and 38,000. Gel filtration of the affinity purified material yielded a single peak labeled by [3H]Q ICS 205-930 with an apparent molecular size of 250,000, which was also composed of two bands of 54,000 and 38,000, consistent with these being the constituents of the 5-HT3 receptor.
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PMID:Purification of the 5-hydroxytryptamine 5-HT3 receptor from NCB20 cells. 238 Jan 74

Zacopride administered orally was more emetic in fed than in fasted ferrets. The emetic activity of zacopride (0.1 mg/kg p.o.) was inhibited (100%) by 0.1 mg/kg i.p. of zacopride and 1 mg/kg i.p. of ICS 205-930. Haloperidol (3.16 mg/kg i.p.) and prochlorperazine (3.16 mg/kg i.p.) were weakly effective. N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, a 5-HT1P antagonist, was inactive. Thus, the emetic activity of zacopride, like that of cisplatin, is blocked by 5-HT3 receptor antagonists.
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PMID:Emetic activity of zacopride in ferrets and its antagonism by pharmacological agents. 238 37

The effects of 5-hydroxytryptamine (5-HT), the 5-HT1-like receptor agonist 5-carboxamidotryptamine and the 5-HT3 receptor agonist 2-methyl-5-hydroxytryptamine were studied on circular muscle strips of the canine terminal ileum and ileocolonic junction. Serial administration of 5-HT or of 5-carboxamidotryptamine induced slow tonic contractions that at higher concentrations of 5-HT (10(-4)-3 x 10(-4] were preceded by an initial relaxation and a fast phasic contraction. The concentration-response curves to both agonists were competitively shifted to the right by the mixed 5-HT1/5-HT2 receptor antagonist methysergide. The initial relaxation and fast phasic contraction were inhibited by the 5-HT3 receptor antagonist ICS 205-930 and tetrodotoxin. Atropine blocked the fast phasic contraction, but enhanced the relaxation. During acetylcholine-induced contractions, 5-HT and 2-methyl-5-hydroxytryptamine (greater than or equal to 10(-5) M), but not 5-carboxamidotryptamine, evoked relaxations that were blocked by ICS 205-930 and tetrodotoxin, but not by adrenoceptor antagonists. Thus, in the canine terminal ileum and ileocolonic junction, 5-HT stimulates neuronal 5-HT3 receptors and excitatory 5-HT1-like receptors located on smooth muscle. Stimulation of the 5-HT3 receptors results in an acetylcholine-mediated contraction and a relaxation mediated by an as yet unknown nonadrenergic noncholinergic neurotransmitter.
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PMID:Pharmacological characterization of 5-hydroxytryptamine receptors in the canine terminal ileum and ileocolonic junction. 238 90

The 5-HT3 hydroxytryptamine receptor from NCB 20 cells was solubilized and the molecular and hydrodynamic properties of the receptor were investigated. The receptor was identified by binding of the radioligand 3-NN'-[3H]dimethyl-8-azabicyclo[3.2.1]octanyl indol-3-yl carboxylate ester [( 3H]Q ICS 205-930) to NCB 20 membranes (Bmax = 1.19 +/- 0.31 pmol/mg of protein; Kd = 0.43 +/- 0.076 nM) and was optimally solubilized with 0.5% deoxycholate. [3H]Q ICS 205-930 labelled one population of sites in solution (Bmax = 1.11 +/- 0.4 pmol/mg of protein; Kd = 0.48 +/- 0.06 nM; n = 4). The characteristics of [3H]Q ICS 205-930 binding were essentially unchanged by solubilization, and competition for [3H]Q ICS 205-930 binding by a series of 5-HT3 agonists and antagonists was consistent with binding to a 5-HT3 receptor site and was similar to that observed for 5-HT3 receptors solubilized from rat brain [McKernan, Quirk, Jackson & Ragan (1990) J. Neurochem. 54, 924-930]. Some physical properties of the solubilized receptor were investigated. The molecular size (Stokes radius) of the [3H]Q ICS 205-930-binding site was measured by gel-exclusion chromatography in a buffer containing 0.2% Lubrol and 0.5 M-NaCl and was determined as 4.81 +/- 0.15 nm (mean +/- S.E.M.; n = 6). Sucrose-density-gradient centrifugation was also performed under the same detergent and salt conditions to determine the partial specific volume (v) of the detergent-receptor site complex. This was found to be 0.794 ml.g-1. Sucrose-density-gradient centrifugation was carried out in both 1H2O and 2H2O to allow correction for detergent binding to the receptor. The Mr of the 5-HT3 receptor under these conditions was calculated as 249,000 +/- 18,000 (n = 3). The size and physical properties of the 5-HT3 receptor are similar to those observed for members of the family of ligand-gated ion channels.
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PMID:Molecular size of the 5-HT3 receptor solubilized from NCB 20 cells. 239 56

1. The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has been reported to have potent effects on gastric smooth muscle in vivo and to enhance gastric emptying in animals and in man. 2. This study investigated the effects of ICS 205-930 on fat-delayed gastric emptying of a semisolid meal and antral motor activity in humans. 3. Twelve healthy men participated in each of three studies in which 10 or 20 mg of ICS 205-930 or placebo were infused i.v. in a random double-blind fashion. Gastric emptying and antral motor activity were studied scintigraphically. 4. Gastric emptying was not altered after 10 mg but slower after 20 mg of ICS 205-930 than after placebo. Emptying after 20 mg of ICS 205-930 was significantly slower than after 10 mg of ICS 205-930. 5. Antral contraction amplitude was slightly lower after 20 mg of ICS 205-930 than after placebo, whereas the effects of 10 mg ICS 205-930 did not differ from those of placebo. 6. The results suggest that the investigated doses of ICS 205-930 have only slight effects on gastric motor activity of healthy young men, with 20 mg reducing the rate of emptying.
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PMID:Effects of the 5-HT3 receptor antagonist ICS 205-930 on fat-delayed gastric emptying and antral motor activity. 239 Apr 31

Agonist-induced desensitization has been utilized to discriminate and independently "isolate" the neuronal excitatory receptors to 5-hydroxytryptamine (5-HT) in the guinea pig ileum (5-HT3 and putative 5-HT4 receptors). Electrically stimulated longitudinal muscle myenteric plexus preparations, and non-stimulated segments of whole ileum were used. Exposure to 5-methoxytryptamine (10 mumol/l) inhibited completely responses to 5-HT at the putative 5-HT4 receptor without affecting 5-HT3-mediated responses. Conversely, exposure to 2-methyl-5-HT (10 mumol/l) inhibited completely responses to 5-HT at the 5-HT3 receptor without affecting putative 5-HT4-mediated responses. The inhibition with 5-methoxytryptamine and 2-methyl-5-HT, either alone or in combination, appeared selective as responses to KCl, DMPP, carbachol, histamine, and substance P were unaffected or only very slightly modified. Furthermore, the pA2 values for ICS 205-930 at the putative 5-HT4 (pA2 = 6.2 to 6.5) and 5-HT3 (pA2 = 7.6 to 8.1) receptors (estimated in the presence of 2-methyl-5-HT and 5-methoxytryptamine, respectively) were consistent with those estimated in the absence of desensitization. 5-Methoxytryptamine, but not 2-methyl-5-HT, suppressed completely but reversibly the concentration-effect curve to renzapride, suggesting that responses to this agent are mediated exclusively via agonism at the putative 5-HT4 receptor. It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT4 receptor from the 5-HT3 receptor in guinea pig ileum. This finding is of importance as no selective antagonist exists for the putative 5-HT4 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum. 240 3

Electrophysiological effects of the 5-HT3 receptor antagonist ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester] were investigated in guinea pig isolated heart preparations. ICS 205-930 prolonged the functional refractory period and decreased the force of contraction in left driven atria. It decreased spontaneous beating rate in right atria. These effects were concentration dependent between 3 X 10(-6) and 10(-4) mol/l of ICS 205-930. In fast action potentials of papillary muscles ICS 205-930 concentration-dependently depressed Vmax and prolonged the action potential duration (APD) between 10(-6) and 10(-5) mol/l. The action potential amplitude (APA) and the resting membrane potential (RMP) remained unchanged. In papillary muscles partially depolarized by high K+ (22 mmol/l) and reactivated by high voltage stimulation, slow response APs were prolonged by ICS 205-930 10(-6) to 3 X 10(-5) mol. Vmax, APA and RMP were not affected. Similar effects on APD were obtained with sotalol (3 X 10(-5) mol/l), an inhibitor of outward K+ current. The slow-APD prolongation induced by ICS 205-930 as well as by sotalol was reversed by BRL 34915 (6-cyano-3,4-dihydro-2,2-dimethyltrans-4-(2-oxo-1-pyrrolidyl )-2H-benzo[b]pyran-3-ol), known to open K+ channels. BRL 34915 alone reduced slow-APD stereoselectively. The results suggest that ICS 205-930 may inhibit and BRL 34915 may stimulate the K+ conductance of guinea pig myocardial cell membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for inhibition by ICS 205-930 and stimulation by BRL 34915 of K+ conductance in cardiac muscle. 244 30

Flat sheet preparations of the mucosa plus submucosa from the guinea-pig ileum were placed in Ussing chambers so that short circuit current (Isc), an index of electrolyte movement across the mucosa, could be measured. In these preparations, 5-hydroxytryptamine (5-HT) increases Isc indirectly by stimulating both cholinergic and non-cholinergic secretomotor neurons. The 5-HT3 receptor antagonist, ICS 205-930 (10(-13)-10(-5 M), substantially depressed the secretory response due to 5-HT (10(-6) M), but not that produced by direct activation of muscarinic receptors on the mucosal epithelium with carbachol (10(-6) M), or by stimulation of secretomotor neurons with substance P (10(-8) M) or 1,1-dimethyl-4-phenylpiperazinium (10(-5)M). The residual response to 5-HT, after the addition of a maximally effective concentration of ICS 205-930 (10(-6) M), was further reduced by hyoscine (10(-7) M). When that part of the 5-HT response attributable to the release of acetylcholine was blocked by hyoscine (10(-7) M), ICS 205-930 did not further modify the response to 5-HT. The hyoscine-resistant component was, however, substantially depressed by tetrodotoxin (3.5 x 10(-7) M). The response remaining after ICS 205-930 and hyoscine was not affected by methysergide (2 x 10(-5) M) or cyproheptadine (10(-7) M). We conclude that there are ICS 205-930 sensitive 5-HT receptors on cholinergic secretomotor neurons, and ICS 205-930, methysergide, and cyproheptadine insensitive 5-HT receptors on non-cholinergic secretomotor neurons.
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PMID:Evidence for two types of 5-hydroxytryptamine receptor on secretomotor neurons of the guinea-pig ileum. 247 54

The effect of two potent and specific antagonists of 5HT3 receptors, ICS 205-930 and MDL 72222, on the reinforcing properties of amphetamine, morphine and nicotine was studied in rats. Drug-induced reinforcement was assessed by measuring drug-conditioned place preference. ICS 205-930 and MDL 72222 dose-dependently reduced the place preference induced by morphine (1.0 mg/kg SC). At doses of 0.030 mg/kg SC the two antagonists completely blocked morphine-induced place preference while doses of 0.015 mg/kg SC significantly reduced it. ICS 205-930 and MDL 72222 at doses of 0.030 mg/kg SC also prevented the place preference induced by nicotine (0.6 mg/kg SC). In contrast, ICS 205-930 and MDL 72222 up to doses of 0.030 mg/kg SC failed to modify the place preference elicited by amphetamine (1.0 mg/kg SC). The results indicate that 5HT3 receptors are specifically involved in the reinforcing properties of morphine and nicotine.
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PMID:5HT3 receptor antagonists block morphine- and nicotine- but not amphetamine-induced reward. 249 25


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