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)

5-HT3 receptors have an exclusive neuronal location and evidence is presented of their involvement in behaviour. 5-HT3 receptor antagonists such as ondansetron, tropisetron and zacopride have provided the critical pharmacological tools to reveal a potent and efficacious ability to regulate disturbed behaviour. Thus the 5-HT3 receptor antagonists will restore to normal rodent and primate behaviour disturbed by increasing limbic dopamine function, aversive situations, cognitive impairments and drug abuse. The remarkable feature of their action is a failure to modify normal behaviour. This unique pharmacological signature has ensured a wide interest in the potential role of the 5-HT3 receptor antagonists in the treatment of schizophrenia, anxiety, age related memory impairment and the problems of withdrawal from drugs of abuse. The preclinical data and preliminary clinical observations are presented.
Pharmacol Toxicol 1992 Dec
PMID:Astra Award Lecture. The psychopharmacology of 5-HT3 receptors. 136 67

Serotonin (5-HT) stimulates phosphoinositide (PI) turnover in rat fronto-cingulate cortical slices and is probably mediated through the activation of both 5-HT2 and 5-HT3 receptors. We have extended these findings and have assessed whether the increased stimulation of PI turnover is secondary to 5-HT stimulated arachidonate metabolism or to the release of another neurotransmitter. Incubation of the cortical slices by the two 5-HT3 receptor agonists, 2-methyl-serotonin (2-Me-5-HT) and phenylbiguanide (PBG), significantly decreases serotonin-stimulated phosphoinositide turnover, indicating that activation of 5-HT3, receptors by 2-Me-5-HT and PBG caused the desensitized PI hydrolysis to 5-HT. Indomethacin did not affect the increased PI hydrolysis induced by 5-HT, 2-Me-5-HT and PBG, suggesting that neither cyclooxygenase nor lipoxgenase activity is required for the PI response and that it is independent of arachidonic acid metabolism. The stimulation in PI turnover induced by 5-HT and the 5-HT3 receptor agonists was not potentiated by proteinase inhibitors suggesting that the release of a peptide neurotransmitter is not involved in the PI response. In addition, the effects of 5-HT, 2-Me-5-HT and PBG on PI turnover are additive to the effect of KCl and veratrine. In conclusion, our results indicate that the action of 2-Me-5-HT and PBG on PI turnover is direct.
Neuroreport 1992 Dec
PMID:Biochemical characterization of phosphoinositide hydrolysis stimulated by 5-HT3 receptor agonists. 136 96

5-HT3 receptor antagonists such as ondansetron, granisetron, ICS205-930 and zacopride are highly effective in the ferret, cat or dog to prevent emesis caused by cisplatin and other chemotherapeutic agents, and radiation treatment. The anti-emetic effects may be mediated centrally in the area postrema and associated structures of the emetic reflex such as the nucleus tractus solitarius, which have a very high density of 5-HT3 receptors. Additional sites of action may be found on the 5-HT3 receptors located on the vagus nerve or enteric neuronal elements in the gastro-intestinal tract. The precise site(s) and mechanism(s) of action of different cytotoxic treatments to induce emesis remains to be determined, but appears to involve a common action on a 5-HT3 system. The 5-HT3 receptor antagonists do not impair normal behaviour and, in particular, fail to affect the extrapyramidal motor system and do not cause sedation. Of potential benefit, the 5-HT3 receptor antagonists have an anxiolytic profile of action in rodent and primate models. The 5-HT3 receptor antagonists are revealed as an important group of drugs to prevent emesis induced by a wide range of cytotoxic treatments.
Br J Cancer Suppl 1992 Dec
PMID:Neuropharmacology of emesis in relation to clinical response. 146 94

The 5-hydroxytryptamine (5-HT)3 receptor blocking properties of YM060, [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride], were examined by electrophysiological and radioligand binding studies. Results were compared with those for ondansetron, granisetron and the enantiomer (S-form) of YM060. 5-HT and 2-methyl-5-HT, a selective 5-HT3 receptor agonist, induced dose-dependent depolarizations of rabbit nodose ganglion with ED50 values of 24.0 (19.9-29.1) and 40.1 (30.9-52.1) nmol, respectively (geometric mean, 95% CL). YM060, ondansetron, granisetron and the S-form dose-dependently inhibited 5-HT-induced depolarizations with IC50 values of 3.85 (2.47-5.98), 1.55 (1.26-1.91), 1.45 (1.18-1.79) and 13.5 (11.2-16.2) nM, respectively. Methysergide, a 5-HT1-like and 5-HT2 receptor antagonist, at a concentration of 10(-5) M had no effect on responses to 5-HT. YM060 up to 10(-5) M produced no significant depression of depolarizing responses to 1,1-dimethyl-4-phenylpiperazinium iodide and gamma-aminobutyric acid. YM060, ondansetron, granisetron and the S-form displaced specific binding of [3H]GR65630 to N1E-115 neuroblastoma cell membranes with Ki values of 0.091 (0.086-0.097), 7.03 (5.96-8.01), 2.02 (1.74-2.30) and 10.3 (9.96-10.6) nM, respectively. These results show that YM060, compared with ondansetron and granisetron, has considerably higher affinity for 5-HT3 receptors in N1E-115 cells and slightly less potent 5-HT3 receptor antagonistic activity in rabbit nodose ganglion. Moreover, the isomeric activity ratio (R-form/S-form) was approximately 112 in N1E-115 cells and no greater than 4 in the ganglion.(ABSTRACT TRUNCATED AT 250 WORDS)
J Pharmacol Exp Ther 1992 Dec
PMID:Characterization of YM060, a potent and selective 5-hydroxytryptamine3 receptor antagonist, in rabbit nodose ganglion and N1E-115 neuroblastoma cells. 146 24

The present paper compares the effects of different serotonergic agonists and antagonists with benzodiazepine derivatives in two animal models of anxiety; the Vogel's and the open-field tests. In the Vogel's conflict test, both diazepam and midazolam produced an anti-punishment action. The drugs 8-OH-DPAT (0.025 and 0.05 mg/kg), buspirone (0.62 mg/kg), gepirone and ipsapirone (0.3 and 0.62 mg/kg, respectively) increased punished intake of water. Ritanserin disinhibited the behaviour of rats at the doses of 2.5 and 5.0 mg/kg and ICS 205-930 (0.001 and 0.01 mg/kg) exerted a marked increase in punished drinking, while ondansetron was active only after the largest dose (1.5 mg/kg). In the open-field test, all drugs increased the number of entries into the central area, as well as the time spent in the central sector of the open-field. The present data indicate similar but not identical spectra of pharmacological sensitivity of both ethologically-oriented and conflict tests, for various classes of anxiolytic drugs. The 5-HT1A receptor agonists and 5-HT2 receptor antagonist have been shown to have similar anxiolytic-like profile to the benzodiazepines but in a narrower dose-range. The 5-HT3 receptor antagonists appeared to be unique in respect to their very strong anti-emotional activity (ICS 205-930), devoid of any clear-cut general inhibitory properties upon locomotion.
Neuropharmacology 1992 Dec
PMID:The comparison of benzodiazepine derivatives and serotonergic agonists and antagonists in two animal models of anxiety. 147 Mar 1

In the present study, the emetic effect of the anticancer drug cisplatin, and protective effects of 5-HT3 receptor antagonists against cisplatin emesis were investigated in the pigeon. The experimental setting involved the i.v. administration of drugs and subsequent observation of the percentage of vomiting animals and number of emetic episodes per vomiting animal over a period of 5 h. In some experiments, the 5-HT and 5-HIAA content in tissues was estimated by the HPLC technique. It was observed that cisplatin (2.5-10 mg/kg) is able to induce dose-dependent emesis in the pigeon. 5-HT3 receptor antagonists (500 micrograms/kg) afford partial protection against cisplatin emesis, although some of them, i.e. indolic derivatives and zacopride, display intrinsic emetic activity at doses of 50-500 micrograms/kg. A serotonergic mechanism appears to be involved in both cisplatin- and 5-HT3 receptor antagonist-induced emesis, since pretreatment with an inhibitor of 5-HT synthesis, para-chlorophenylalanine (300 mg/kg x 3 days), is able to hamper vomiting induced by either cisplatin or 5-HT3 receptor antagonists. It is concluded that the intrinsic emetic effects of 5-HT3 receptor antagonists in the pigeon provide pharmacological evidence of species differences in the properties of 5 HT3 receptors.
Toxicol Lett 1992 Dec
PMID:A dual effect of some 5-HT3 receptor antagonists on cisplatin-induced emesis in the pigeon. 147 Dec 30

Supraspinal opioid analgesia is mediated in part by connections between the midbrain periaqueductal gray (PAG) and the ventral-medial medulla, including the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis (NRGC). A serotonergic synapse appears to participate in this pathway since methysergide microinjected into the NRM-NRGC significantly reduced morphine analgesia elicited from the PAG. The present study evaluated the role of specific serotonin receptor subtypes by pretreating rats with microinjections of either the 5HT2 antagonist, ritanserin or the 5HT3 antagonist, ICS205930, into the NRM-NRGC and examining their effects upon morphine (2.5 micrograms) analgesia elicited from the PAG. Mesencephalic morphine analgesia was significantly reduced following pretreatment with both ritanserin (0.25-2.5 micrograms) on the tail-flick (81%) and jump (65%) tests and ICS205930 (0.25-5 micrograms) on the tail-flick (91%) and jump (63%) tests. Neither ritanserin nor ICS205930 altered basal nociceptive thresholds. Medullary placements ventral or lateral to the NRM/NRGC failed to support these antagonistic effects. These data indicate that ventro-medial medullary 5HT2 and 5HT3 serotonergic receptors modulate the transmission of opioid pain-inhibitory signals from the PAG.
Brain Res 1992 Dec 04
PMID:Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. 147 4

Intracellular recording methods were used to study the actions of 5-hydroxytryptamine (5-HT) on 257 myenteric neurons in the guinea pig gastric antrum. Application of 5-HT caused three types of postsynaptic responses. A fast-activating depolarizing response was accompanied by a decreased input resistance and desensitized quickly to repeated applications. It was mediated by a 5-HT3 receptor. A slowly activating depolarization, accompanied by an increase in the input resistance and enhancement of the excitability, was mainly observed in after hyperpolarizing/type 2 neurons. It was suppressed by the prokinetic benzamide compound renzapride, while classical 5-HT1-4 receptor antagonists had no effect, suggesting the involvement of a 5-HT1p receptor as described in small intestinal neurons. A long-lasting hyperpolarizing response, accompanied by a decreased input resistance, was observed in a small subset of neurons. This response seemed to be mediated by a 5-HT1a receptor. Superfusion of 5-HT caused a dose-dependent inhibition of the stimulus-evoked nicotinic cholinergic fast excitatory postsynaptic potential (EPSP), which was mediated by a presynaptic 5-HT1a receptor. 5-HT also presynaptically inhibited the slow EPSP.
Am J Physiol 1992 Dec
PMID:Actions of 5-hydroxytryptamine on myenteric neurons in guinea pig gastric antrum. 147 91

A series of esters and amides of 1-alkyl-2-oxo-1,2-dihydroquinoline-4- carboxylic acid or 2-alkoxy-quinoline-4-carboxylic acid containing a basic azabicycloalkyl moiety has been synthesized and evaluated for affinity for the [3H]quipazine-labeled 5-HT3 receptors. Most of the esters exhibited 10-fold more potent activity than that of ondansetron (1; Ki = 7.6 nM). Lipophilic substituents at the 1- or 2-position of the quinoline ring enhanced affinity for the receptors. Compounds 21 and 37 showed the highest affinity (Ki = 0.32 and 0.31 nM, respectively) among them. On the other hand, most of the amides showed 100-fold lower affinity than that of the esters. Molecular modeling studies indicated that the carbonyl moiety in 19 (ester) or 31 (amide) was not coplanar to the plane of an aromatic ring (over 20 degrees deviation). Although some of the selected compounds exhibited potent activity in the Bezold-Jarisch (B-J) reflex test, good correlation was not observed between the affinity for the 5-HT3 receptors and the activity in the B-J reflex test (in vivo). From these data, it was suggested that our quinoline derivatives might interact with the 5-HT3 receptors in a different way from that of the reported 5-HT3 receptor antagonists presumably due to the presence of the heterogeneity of the 5-HT3 receptors between brain and heart.
J Med Chem 1992 Dec 25
PMID:5-HT3 receptor antagonists. 1. New quinoline derivatives. 147 89

The incidence, severity, and onset of radiation-induced emesis (RIE) are related to field size, site, and dose per fraction. Radiation-induced emesis can occur (1) within 2 to 3 weeks in approximately 50% of patients after conventional fractionated radiotherapy (200 cGy/fraction) to the upper abdomen, (2) acutely in more than 90% of patients receiving fractionated total body irradiation (TBI) for bone marrow transplantation, and (3) within 30 to 60 minutes in more than 80% of patients following single high-dose (> 500 cGy)/large field hemibody irradiation (HBI). The increased frequency of emesis associated with TBI and HBI has renewed the interest in the mechanism and treatment of RIE. A number of studies have reported a significant difference in the incidence of emesis following doses of > or = 500 cGy to the upper-mid (> 80%) and lower (20% to 40%) hemibody. The data suggested that the organ responsible for emetic response was in the upper abdomen. However, the mechanism of RIE is not well understood, although degradation products from normal tissues and tumor have been suggested. The introduction and effectiveness of the 5-hydroxytryptamine3 receptor antagonists in chemotherapy-induced emesis and the location of these receptors in the upper abdomen (possible site of the radiation-associated emetic response) suggested that this group of compounds may have a role in RIE. Lucraft and Palmer (Clin Radiol 33:621-622, 1982) reported no differences between levonantradol and chlorpromazine in preventing RIE in patients treated with single doses of more than 10 Gy to a small upper abdominal field. Priestman (Eur J Cancer Clin Oncol 25:529-533, 1989 [Suppl]) reported on a pilot and randomized study with ondansetron after single doses of 8 to 10 Gy to the upper abdomen. In the pilot study, ondansetron achieved major or complete control of vomiting in 77% to 90% of patients; subsequently, he reported a significant difference between ondansetron (97%) and metoclopramide (45%) in controlling RIE on the day of radiotherapy. Hewitt et al (Bone Marrow Transpl 7:431-433, 1991) reported a complete or major response on 93% of the days of ondansetron therapy during pretreatment therapy with cyclophosphamide and TBI for bone marrow transplantation. A preliminary analysis of 41 patients treated with HBI at the Rex Cancer Center confirms the role of ondansetron in RIE. Twenty-eight patients (upper-mid 16 patients/lower HBI 12 patients) did not receive pretreatment antiemetics (group A); seven received non-ondansetron pre-HBI (group B); and six received ondansetron (group C).(ABSTRACT TRUNCATED AT 400 WORDS)
Semin Oncol 1992 Dec
PMID:Radiation-induced emesis: effects of ondansetron. 148 81


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