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 selective dopamine D-1 receptor antagonist SCH 23390 has been tested in vitro in the rat fundus model and in vivo in the electrically stimulated flexor reflex model. In the fundus model, SCH 23390 showed a potent agonistic activity compared to that of different 5-HT receptor agonists. Pindolol, 1-propranolol and pirenperone showed no or only weak inhibition of the SCH 23390-induced contractions in the fundus strip whereas methysergide was a potent inhibitor. The 5-HT3 receptor antagonist ICS 205-930 did not induce an inhibitory effect. In the electrically stimulated flexor reflex model in pithed rats, SCH 23390 induced a marked increase of the reflex. This increase was slightly inhibited by a mixed dopamine (DA) D-1/D-2 antagonist cis(Z)-flupentixol and by a specific DA D-2 antagonist YM 09151-2. Different reference antagonists: bicuculline (GABAergic), propranolol (beta-adrenergic), scopolamine (muscarinic), yohimbine (alpha 2-adrenergic), prazosin (alpha 1-adrenergic) were all without an antagonist effect on the SCH 23390-induced increase of the flexor reflex. Ketanserin, a selective 5-HT2 receptor antagonist, showed a weak and short-lasting inhibition of the SCH 23390 effect in high doses, whereas ritanserin showed only 35% inhibition of the SCH 23390-induced flexor reflex at a dose of 1.3 mumol/kg i.v. The mixed 5-HT1/5-HT2 antagonists methiothepin and metergoline showed a marked inhibitory effect at 2.6 mumol/kg i.v. and 3.1 mumol/kg i.v., respectively (1.3 mg/kg i.v.). These findings suggest that SCH 23390 might possess 5-HT1 receptor agonist activity.
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PMID:SCH 23390--a selective dopamine D-1 receptor antagonist with putative 5-HT1 receptor agonistic activity. 296 72

1. This paper describes the pharmacology of the novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist GR38032F. 2. On the isolated vagus nerve and superior cervical ganglion of the rat, R,S-GR38032F behaved as a reversible competitive antagonist of 5-HT-induced depolarization with pKB values of 8.61 +/- 0.08 (n = 19) and 8.13 +/- 0.07 (n = 16), respectively. The resolved R- and S-isomers of GR38032F were approximately equipotent as 5-HT antagonists on the rat vagus nerve: the pKB values were 8.95 +/- 0.05 (n = 16) and 8.63 +/- 0.08 (n = 17), respectively. R,S-GR38032F was also an effective antagonist of 5-HT on the rabbit isolated vagus nerve: in this case the pKB value was 9.40 +/- 0.14 (n = 4). 3. On the rabbit isolated heart, low concentrations of R,S-GR38032F (3 X 10(-11)-1 X 10(-9) M) antagonized the positive chronotropic effect of 5-HT and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT). However, the effects of the compound did not appear consistent with simple reversible competition. 4. On the longitudinal smooth muscle of the guinea-pig ileum, R,S-GR38032F caused concentration-dependent parallel rightward displacement of the 2-methyl-5-HT concentration-contraction response curve; in contrast, a portion of the response to 5-HT appeared resistant to R,S-GR38032F. pKB values estimated from the effects of the compound against 2-methyl-5-HT or the inhibitable portion of the response to 5-HT were 7.31 +/- 0.06 (n = 8) and 7.33 +/- 0.13 (n = 8), respectively. Against 2-methyl-5-HT, R-GR38032F seemed more potent (pKB 7.20 +/- 0.10; n = 6) than S-GR38032F (pKB 6.30 +/- 0.05; n = 6). 5. R,S-GR38032F is highly selective for 5-HT3 receptors, and at concentrations of 3 X 10(-6)-3 X 10(-5) M, had negligible agonist or antagonist activity on other 5-HT or non-5-HT receptor-containing tissues on which it was tested. 6. The potency and duration of action of R,S-GR38032F in blocking 5-HT3 receptors in vivo were assessed by measuring its ability to antagonize the bradycardic response to 5-HT or 2-methyl-5-HT administered intravenously (i.v.) to anaesthetized animals. For i.v. administration to the rat, the ED50 for R,S-GR38032F against 2-methyl-5-HT (100pgkg-1) was 0.4 (95% confidence limits 0.18- 0.87) ygkg-1 (n = 10); the corresponding value for oral administration to this species was 7.0 (3.0- 22.0)pgkg-' (n = 8-10 per dose level). R,S-GR38032F was similarly effective in the anaesthetized cat. 7. The present results are discussed with reference to the postulated existence of subtypes of the 5-HT3 receptor.
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PMID:Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors. 296 67

The effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by L-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced L-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by L-5-HTP are mediated by 5-HT2 receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT2 receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT.
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PMID:Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists. 311 4

The antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick latency. This action was blocked by 5-HT3 and gamma-aminobutyric acidA (GABAA) receptor antagonists but not by 5-HT2, 5-HT1A, 5-HT1B or 5-HT1S receptor antagonists. Binding studies indicated that 5-MeO-DMT had very low affinity for 5-HT3 receptors. 5-MeO-DMT inhibited biting behavior while increasing scratching behavior induced by intrathecally administered substance P. The inhibition of biting behavior was antagonized by intrathecal co-administration of 5-HT1B and GABAA receptor antagonists while 5-HT1A, 5-HT1S, 5-HT2 and 5-HT3 receptor antagonists had no effect. 5-MeO-DMT-enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline, suggesting the involvement of 5-HT1A, 5-HT1B, 5-HT1S, 5-HT3 and GABAA receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT1B, 5-HT3 and GABAA receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin).
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PMID:Intrathecal 5-methoxy-N,N-dimethyltryptamine in mice modulates 5-HT1 and 5-HT3 receptors. 750 56

1. In isolated goat middle cerebral artery segments, 5-hydroxytryptamine (5-HT, 10(-8)-3 x 10(-5) M) elicited concentration-dependent contractions with EC50 = 2.1 (1.9-2.5) x 10(-7) M and Emax = 64 +/- 2% of 50 mM KCl-induced contraction. 2. Several 5-HT receptor agonists were used: (a) the agonist of 5-HT2 receptors alpha-methyl-5-hydroxy-tryptamine (10(-7)-3 x 10(-4) M) induced strong contraction (51 +/- 6%); (b) the selective agonists of 5-HT1 receptors sumatriptan (10(-8)-10(-5) M) and 5-carboxamidotryptamine (10(-9)-10(-4) M) and the agonist of 5-HT1A receptors 8-hydroxy-2-(di-n-propylamino)tetralin (10(-7)-3 x 10(-5) M) induced weak contractions (8, 18 and 14%, respectively); and (c) the agonist of 5HT3 receptors 2-methyl-5-hydroxytryptamine (3 x 10(-6)-10(-4) M) induced almost negligible contraction. 3. Pretreatment with the antagonist of 5-HT1A and 5-HT1B receptors cyanopindolol (10(-8), 10(-6) M), the antagonist of 5-HT1/5-HT2 receptors methysergide (10(-11), 10(-9) M) and the antagonist of 5-HT2 receptors ketanserin (10(-11), 10(-9) M) induced non-competitive inhibition of the concentration-response curve to 5-HT. The antagonist of 5-HT3 receptors 3-trophanyl-3,5-dichlorobenzoate (10(-7), 10(-5) M) did not inhibit the contractile curve to 5-HT. 4. These results suggest that 5-HT contracts the goat middle cerebral artery by acting mainly on 5-HT2 receptors.
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PMID:Characterization of 5-hydroxytryptamine receptors in goat cerebral arteries. 759 Jan 17

Synthesis and pharmacological evaluation of a series of condensed quinoline derivatives bearing a basic nitrogen on piperazine or [(dimethylamino)ethyl]thio moieties attached at the 2-position of the quinoline nucleus are described. 5-HT receptor binding studies revealed, for most of the compounds studied, nanomolar affinity for the 5-HT3 receptor subtype. The most active compound, benzopyrano[3,4-c]quinoline derivative 5f, displayed a Ki value very similar to that reported for quipazine along with an improved selectivity. Functional and in vivo testing carried out on three selected compounds showed that 5f,j,n are potent 5-HT3 receptor antagonists with potencies in the same range as the best known 5-HT3 receptor antagonists ondansetron, tropisetron, and zacopride. The crystal and molecular structures of compounds 5f,j,n were determined by single-crystal X-ray diffraction and used as starting structures for molecular modeling studies. Comparative molecular field analysis (CoMFA) was applied to binding constants of compounds 5a-p and 6a-h. The cross-validated r2, derived from partial least-squares calculations, indicated a good predictive capacity for affinity values in the series of compounds investigated. Evidence for the prediction capacity is provided in the form of plots of actual vs predicted pKi values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.
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PMID:Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton: synthesis, structure, biological activity, and comparative molecular field analysis studies. 762 8

5-Hydroxytryptamine (5-HT) receptor agonists and antagonists were dosed intravenously (i.v.) and studied for their effects on the depressor cardiovascular pseudoaffective reflex evoked by acute noxious colo-rectal distension in the anaesthetized rat. Methiothepin (100 micrograms kg-1) caused an initial, unsustained blockade of evoked depressor responses whilst ketanserin (100 micrograms kg-1) was without effect. By comparison, ondansetron dose dependently inhibited evoked depressor responses and was maximally active at 100 micrograms kg-1, causing a 57.5 +/- 0.9% reduction. An ID50 value of 36.7 micrograms kg-1 was estimated by regression analysis. In contrast, granisetron caused complete blockade of the depressor response with an ID50 of 0.4 microgram kg-1. Bell-shaped dose-effect curves were demonstrated for both granisetron and ondansetron. Intrathecal dosing with granisetron (100 ng) into the thoracolumbar region of the spinal cord prevented the depressor response to colo-rectal distension, suggesting a spinal site of action. The pseudoaffective depressor responses were not facilitated by pre-dosing with the 5-HT receptor agonists, 8-OH DPAT, alpha-methyltryptamine or 1-phenyl-biguanide. However, 8-OH DPAT (100 micrograms kg-1) facilitated pressor responses. It is suggested that 5-HT3-like receptors may have a role in modulating depressor responses to visceral pain and that in this action different 5-HT3 receptor antagonists are not necessarily equi-effective.
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PMID:5-Hydroxytryptamine3 receptor antagonism modulates a noxious visceral pseudoaffective reflex. 763 Apr 81

The purpose of this review is to describe the consequences of antidepressant treatment on the behaviour of rodents after activation of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes. In a summary table, the involvement of 5-HT receptors in inducing behavioural changes are described. It is emphasized that these effects are not always only exclusively linked to serotonergic functions nor that they are only initiated by central 5-HT receptors. Hereafter, the complex mutual inhibitory effects of 5-HT receptor subtype-mediated processes are discussed by interpreting effects of antagonists and describing the different effects of low and high doses of mixed 5-HT1C/5-HT2 receptor agonists. Mutual influences are seen particularly with 5-HT1A, 5-HT1C and 5-HT2, but not with 5-HT1B, 5-HT1D or 5-HT3 receptor-mediated effects. It is shown that the behavioural consequences of 5-HT1A, 5-HT1C and 5-HT2 receptor stimulation may be changed by brain lesions or chronic treatment with drugs. Among these drugs are the antidepressants. Finally, 5-HT receptor function in depressed patients is discussed, and the hypothesis is proposed that an important function of antidepressants is to restore a disturbed balance between 5-HT1A, 5-HT1C and 5-HT2 receptors in depressed patients.
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PMID:Interactions between 5-hydroxytryptamine receptor subtypes: is a disturbed receptor balance contributing to the symptomatology of depression in humans? 763 Sep 28

Since the discovery of serotonin receptor subtypes in 1957, the classification of serotonin receptors now includes 5-HT1 through 5-HT7 receptors, with further subtypes of receptors in each family. Unique among this expanding group of 5-HT receptor subtypes is the 5-HT3 receptor, which is the only known 5-HT receptor that directly gates an ion channel. The channel conducts primarily Na+ and K+, resulting in rapid depolarization followed by a rapid desensitization. The immediate consequence of neuronal depolarization resulting from 5-HT3 receptor activation is the release of stored neurotransmitter. The subsequent release of stored neurotransmitter, particularly dopamine in the mesolimbic pathways, suggest a potentially important role for this receptor system in neuronal circuitry involved in drug abuse. The following review broadly covers the structure, function and distribution of the 5-HT3 receptor system in the CNS and data addressing the potential role of this receptor system in modulating the effects of a wide variety of abused drugs. Most of the evidence indicates an association between the ability of 5-HT3 antagonists to decrease mesolimbic dopamine levels and to attenuate the psychomotor stimulant effects of drugs. However 5-HT3 receptor antagonists are less robust at attenuating other drug effects that are believed to be related to their abuse liability, such as discriminative stimulus and reinforcing effects. The one exception may be ethanol, which directly potentiates the effects of 5-HT at the 5-HT3 receptor channel complex. In addition to the implications of an interaction with the mesolimbic dopaminergic system, the ability of 5-HT3 receptor antagonists to function as anxiolytics suggest they could be useful pharmacotherapies during drug withdrawal. However, further studies are needed since currently available 5-HT3 receptor antagonists do not have uniform behavioral effects, may interact with other receptor systems, and have atypical dose-response effects.
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PMID:The role of 5-HT3 receptors in drug dependence. 767 67

Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five 5-HT1-like receptors, three 5-HT2 receptors, one 5-HT3 receptor, two 5-HT5 receptors, one 5-HT6 receptor and one 5-HT7 receptor. Molecular biological information on the 5-HT4 receptor is notably absent from this list. We now report the cloning of the pharmacologically defined 5-HT4 receptor. Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence. The corresponding full length cDNA was isolated from a rat brain cDNA library. Transiently expressed in COS-7 cells, this receptor stimulates adenylyl cyclase activity and is sensitive to the benzamide derivative cisapride. The response is also blocked by ICS-205930. Interestingly, we isolated two splice variants of the receptor, 5-HT4L and 5-HT4S, differing in the length and sequence of their C-termini. In rat brain, the 5-HT4S transcripts are restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely detectable. In peripheral tissues, differential expression was also observed in the atrium of the heart where only the 5-HT4S isoform was detectable.
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PMID:The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants. 779 7


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