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)

Latent inhibition (LI) is a behavioral model of selective attention that has been used to study the attentional deficits seen in schizophrenia. In the present study, we examined the effect of 5-hydroxytryptamine3 (5-HT3) receptor blockade on LI using the conditioned emotional response (CER) procedure. Prior exposure to 20, 30, or 40 stimulus presentations significantly, and almost completely, inhibited the CER to that stimulus. This LI effect was much weaker when only 10 preexposures were given. 1H-indole-3-carboxylic acid, trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester methanesulfonate (MDL 73,147EF), a selective 5-HT3 receptor antagonist, significantly facilitated the LI effect observed after 10 preexposures at 0.1 mg/kg but not at 0.01 mg/kg. The magnitude of this effect was comparable to that observed with the classical neuroleptic haloperidol (0.1 mg/kg). Neither MDL 73,147EF nor haloperidol affected the CER in animals not preexposed to the stimulus. These results strongly corroborate suggestions that 5-HT3 receptor antagonists will be of use in the treatment of schizophrenia.
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PMID:MDL 73,147EF, a 5-HT3 antagonist, facilitates latent inhibition in the rat. 140 84

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

YM060 [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimida zol e hydrochloride], is structurally independent of other 5-HT3 receptor antagonists. We investigated in vivo 5-HT3 receptor blocking activity of YM060 and compared results with those of its enantiomer (S-form), ondansetron (GR38032F), granisetron (BRL43694), ICS205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester], LY277359 [endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1] oct-3-yl)-7-benzofuran-carboxamide-(Z)-2-butenedioate (1:1)], Y25130 [(+-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4- dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride] and zacopride [(R,S)4-amino-N-[1-azabicyclo (2.2.2)oct-3-yl]-5-chloro-2-methoxybenzamide(E)-2-butenedioat e]. YM060 injected i.v. dose-dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (von Bezold-Jarisch reflex) with an ED50 value of 0.036 (0.031-0.041) micrograms/kg (n = 3-5). Based on these values, YM060 was 53, 18, 23, 16, 11 and 4 times as potent as ondansetron, granisetron, ICS205-930, LY277359, Y25130 and zacopride, respectively. The S-form of YM060 also inhibited 5-HT-induced bradycardia, but with a potency approximately 250 times less than that of YM060 (R-form). YM060 dosed p.o. also inhibited 5-HT-induced bradycardia with an ED50 value of 0.59 (0.44-0.80) micrograms/kg (n = 3-5), indicating the drug to be 387, 66, 97, 6 and 16 times more potent than ondansetron, granisetron, ICS205-930, LY277359 and Y25130, respectively, but 2 times less potent than zacopride. Bioavailability of YM060 based on the p.o.-to-i.v. ED50 ratio (p.o./i.v. = 16) was lower than those of zacopride (2) and LY277359 (6), similar to that of Y25130 (22) and better than those of ondansetron (109), granisetron (60) and ICS205-930 (71).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serotonin (5-HT)3 receptor blocking activities of YM060, a novel 4,5,6,7-tetrahydrobenzimidazole derivative, and its enantiomer in anesthetized rats. 194 29

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

MDL 73,147EF (1H-indole-3-carboxylic acid-trans-octahydro-3-oxo-2,6- methano-2H-quinolizin-8-yl-ester methanesulphonate) is a potent and selective 5-HT3 receptor antagonist (pA2 9.8, rabbit heart; pIC50 less than 5, D-2 receptor). The effects of acutely and chronically administered haloperidol and MDL 73,147EF were compared in an electrophysiologic model for antipsychotic activity. Haloperidol, but not MDL 73,147EF, given acutely increased the number of active dopamine neurons in the substantia nigra (A9). Both haloperidol and MDL 73,147EF, given chronically, decreased the number of active ventral tegmental dopamine neurons and the number of active A9 dopamine neurons. The results indicate that MDL 73,147EF may prove useful as an antipsychotic with a unique mechanism of action.
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PMID:Effect of acute and chronic MDL 73,147EF, a 5-HT3 receptor antagonist, on A9 and A10 dopamine neurons. 274 86

In pig coronary artery preincubated with [3H]noradrenaline, the effects of serotonin (5-HT) receptor agonists and antagonists on the electrically evoked (0.66 Hz) tritium overflow were determined. Tritium overflow was inhibited by 5-HT, 5-aminotryptamine, N,N-dimethyl-5-hydroxytryptamine, 5-hydroxytryptamine, 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969) and tryptamine. The maximum inhibition obtainable with 5-HT was by about 35%, its pIC20 value was 7.85. 8-Hydroxy-di(n-propylamino)tetralin, urapidil, ipsapirone, 5-carboxamidotryptamine, 4-hydroxytryptamine, 5-methoxytryptamine and alpha-methyl-5-hydroxytryptamine did not decrease 3H overflow. The inhibitory effect of 5-HT was not antagonized by ketanserin, mesulergine, metitepine, propranolol, (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930) and yohimbine. Additionally, it was not altered by indomethacin. We conclude from the present data that the sympathetic nerves of the pig coronary artery are endowed with inhibitory presynaptic 5-HT receptors which do not belong to the 5-HT1, 5-HT2 or 5-HT3 receptor type but seem to represent a so far unknown receptor class.
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PMID:Inhibition of noradrenaline release in the pig coronary artery via a novel serotonin receptor. 275 73

The distribution of 5-hydroxytryptamine receptors of the 5-hydroxytryptamine3 type was examined in human brain post mortem tissue, using quantitative in vitro autoradiography. The selective and potent 5-hydroxytryptamine3 receptor antagonist [3H]ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester] was used as ligand. Highest levels of labelling were found in discrete nuclei of the lower brainstem. At all levels of the spinal cord the substantia gelatinosa was also densely labelled. In contrast, specific binding in the forebrain was very low and concentrated in some regions of the limbic system. The enrichment of [3H]ICS 205-930 binding sites in nuclei of the dorsal medulla and spinal cord is in good agreement with the proposed role for 5-hydroxytryptamine in sensory processing. High densities of 5-hydroxytryptamine3 binding sites in the area postrema support a central site of action for 5-hydroxytryptamine in emesis. Finally, the presence of [3H]ICS 205-930 binding sites in the limbic system provides an anatomical substrate for the behavioural effects of 5-hydroxytryptamine3 receptor antagonists.
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PMID:5-hydroxytryptamine3 receptors in the human brain: autoradiographic visualization using [3H]ICS 205-930. 279 43

The effects of 5-hydroxytryptamine (5-HT) on the release of gamma-aminobutyric acid (GABA) were examined in the longitudinal muscle-myenteric plexus (LM-MP) preparation of guinea-pig ileum. 5-HT increased the spontaneous release and inhibited the electrically-evoked release of [3H]-GABA. The 5-HT-evoked release was Ca2+-dependent and tetrodotoxin-sensitive, and was antagonized by (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930), but not by methysergide and ketanserin. The inhibitory effect of 5-HT was antagonized by methysergide, but not by ketanserin and ICS 205-930. 8-Hydroxy-2-(di-n-propylamino)tetralin mimicked the inhibitory effect of 5-HT. Thus, 5-HT may exert an excitatory effect on the enteric GABAergic neurone via the 5-HT3 receptor and an inhibitory effect via the 5-HT1A receptor.
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PMID:Dual effects of 5-hydroxytryptamine on the release of gamma-aminobutyric acid from myenteric neurones of the guinea-pig ileum. 281 20

The ability of the highly selective 5-HT3 receptor antagonist ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) to block the increase in tail flick (TFL) and hot plate latencies (HPL) produced by intrathecally (i.t.) administered serotonin (5-HT) was examined in pargyline pretreated rats. ICS 205-930 (0.1 microgram, i.t.) blocked the ability of 5-HT (200 micrograms) to increase TFL and HPL. Significant hyperalgesia, as measured by a decrease in TFL and HPL compared to saline controls, also resulted from either the coadministration of ICS 205-930 (10 micrograms) and 5-HT (200 micrograms) or from ICS 205-930 (100 micrograms) alone. These data suggest an important role for 5-HT3 receptors in modulating spinal nociceptive responses.
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PMID:Reversal of the antinociceptive effects of intrathecally administered serotonin in the rat by a selective 5-HT3 receptor antagonist. 322 19

The aim of this study was to investigate the pharmacological characteristics of the 5-hydroxytryptamine-(5-HT)-induced electrical response in cultured neuroblastoma N1E-115 cells of the mouse. In these cells 5-HT induces a transient membrane depolarization, which is associated with a transient inward current, that has been recorded in voltage clamp experiments on whole cells. The peak amplitude of the inward current depends on the concentration of 5-HT applied. Maximum peak inward current was evoked by 10 microM 5-HT and half maximum effect by 2 microM. Responses to 5-HT were blocked by nanomolar concentrations of selective 5-HT3-receptor antagonists, whereas the selective agonist 2-methyl-5-HT mimicked the membrane depolarization induced by 5-HT. A number of agonists and antagonists, which are known to act on 5-HT1-like, 5-HT2, dopaminergic and adrenergic receptors failed to affect the response to 5-HT in neuroblastoma cells. Observed antagonistic effects of SCH 23390 [(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepi n-7-ol hemimaleate] and haloperidol are discussed. The inhibitory effect of the 5-HT3 receptor antagonist, ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester] has been demonstrated. When cells were exposed to 0.1 nM ICS 205-930 the maximum evoked response was reduced by about 50%, but a surmountable shift of the concentration-response curve of 5-HT was not observed. The kinetics of the 5-HT-induced inward current remained unchanged in the presence of ICS 205-930. Recovery from the block by ICS 205-930 was very slow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological characterization of serotonin 5-HT3 receptor-mediated electrical response in cultured mouse neuroblastoma cells. 337 70


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