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)

Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.
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PMID:Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides. 154 79

1. The effect of micromolar concentrations of divalent metal cations on ion current activated by 5-hydroxytryptamine (5-HT) was investigated in NCB-20 neuroblastoma cells by the use of the whole-cell, patch-clamp technique. 2. Ion current activated by 5-HT in these cells was mimicked by 5-HT3 receptor agonists, blocked by nanomolar concentrations of selective 5-HT3 receptor antagonists and reversed polarity at approximately 0 mV. These properties indicate that this current is carried primarily if not exclusively by the nonspecific cation channel activated by the 5-HT3 receptor. 3. The Group IIb metal cations Cd2+ and Zn2+ and the Group Ib cation Cu2+ inhibited 5-HT-activated current with inhibition increasing in a concentration-dependent manner over micromolar concentrations of the ions. The order of potency of the ions for inhibiting 5-HT-activated current was Zn2+ (IC50 = 20 microM) greater than or equal to Cu2+ (IC50 = 25 microM) greater than Cd2+ (IC50 = 75 microM) at -50 mV. The other divalent metal cations tested (Ba2+, Co2+, Mg2+, Mn2+, and Ni2+) produced little or no inhibition of 5-HT-activated current at concentrations up to 200 microM. 4. Inhibition of 5-HT-activated current by Cd2+ and Zn2+ was dependent on membrane potential with the Kd increasing e-fold per 72 and 52 mV, respectively. Inhibition by Cu2+ was much less voltage dependent with the Kd increasing e-fold per 233 mV. 5. Inhibition by all three cations decreased with increasing concentration of agonist over a range of 5-HT concentrations from 1 to 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells. 172 46

YM060, (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, is a new serotonin (5HT)3-receptor antagonist. We examined the effects of YM060 on chemotherapeutic agent-, apomorphine- and copper sulfate-induced emesis. Intravenous YM060 potently prevented cisplatin (10 mg/kg, i.v.)-induced emesis with ED50 values of 0.06 (0.05-0.07) micrograms/kg, i.v. in ferrets. Based on the ED50 values, YM060 was 300, 20 and 100 times more potent than ondansetron, granisetron and the S-isomer of YM060, respectively. The relative potencies of these drugs described above were similar to those in the previously reported 5HT3-receptor antagonism. YM060 given orally also potently inhibited cisplatin (10 mg/kg, i.p.)- and cyclophosphamide (200 mg/kg, i.p.)-induced emesis in ferrets with ED50 values of 0.1 (0.09-0.11) and 0.02 (0.16-0.27) micrograms/kg, p.o., respectively. All tested 5HT3-receptor antagonists including YM060 failed to prevent apomorphine (0.1 mg/kg, s.c.)-induced emesis in dogs and copper sulfate (1%, 10 ml, p.o.)-induced emesis in ferrets. Our data indicate that YM060 is a highly potent inhibitor of chemotherapeutic agent-induced emesis and that the antiemetic effect of YM060 may be depend on 5HT3-receptor antagonism.
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PMID:Antiemetic effects of YM060, a potent and selective serotonin (5HT)3-receptor antagonist, in ferrets and dogs. 181 64

The intravenous injection of cisplatin (10 mg/kg), the subcutaneous injection of apomorphine (0.125-1 mg/kg) and lisuride (0.001-0.1 mg/kg), the oral administration of ipecacuanha (0.3-2.4 mg/kg) and the intragastric administration of copper sulphate (25-100 mg/kg), induced a vomiting and retching response in the ferret. Pretreatment with dl-fenfluramine (5 mg/kg i.p.) prevented or reduced the emesis induced by cisplatin, apomorphine, ipecacuanha and lisuride but failed to significantly antagonise copper sulphate-induced emesis. The 5-HT3 receptor antagonist ICS 205-930 (0.1 mg/kg i.p.) prevented emesis induced by cisplatin and ipecacuanha but failed to prevent or significantly reduce the emesis induced by apomorphine, lisuride or copper sulphate. Dopamine receptor antagonists, including fluphenazine (0.1-1.0 mg/kg i.p.) prevented apomorphine- and lisuride-induced emesis but were less potent or had inconsistent actions to antagonise cisplatin- or ipecacuanha-induced emesis and failed to inhibit the emesis induced by copper sulphate. The data indicate that dopamine and/or 5-HT3 receptor systems are involved in drug-induced emesis but that emesis caused by gastric irritation induced by copper sulphate is mediated by different receptor mechanisms.
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PMID:Fluphenazine, ICS 205-930 and dl-fenfluramine differentially antagonise drug-induced emesis in the ferret. 197 49

Antiemetic effects of serotonin 5-HT3 receptor antagonists (ICS205-930, zacopride, BRL43694, GR38032F) were investigated in Suncus murinus. Veratrine, nicotine, copper sulfate, cisplatin, cyclophosphamide and motion sickness were used as emetic stimuli. Serotonin 5-HT3 receptor antagonists did not inhibit emetic responses to veratrine, nicotine, copper sulfate and motion sickness. However, cisplatin- and cyclophosphamide-induced emesis was strongly blocked by them. Both subcutaneous and intravenous injections of 5-HT3 antagonists were effective. Serotonin 5-HT1 and 5-HT2 receptor antagonists were less effective. These results clearly indicate that a 5-HT3 receptor-mediated mechanism(s) is involved in the emesis caused by cancer chemotherapeutic agents and that 5-HT3 receptor antagonists are very effective as prophylactic drugs.
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PMID:Selective blockade of cytotoxic drug-induced emesis by 5-HT3 receptor antagonists in Suncus murinus. 204 Dec 20

In the ferret, 5-HT3 receptor antagonists are effective in controlling emesis produced by cytotoxic agents or radiation. To investigate the possibility that substance P has a role, as well as 5-HT, in the emetic reflex pathway, we have examined the anti-emetic effects of a NK1 receptor antagonist (racemic CP-99,994) in the ferret. Racemic CP-99,994 was effective against a range of emetogens, comprising cytotoxic drugs, radiation, morphine, ipecacuanha and copper sulphate.
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PMID:Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets. 750 63

We have examined the ability of divalent cations to inhibit 3H-GR 65630 binding to 5-HT3 receptor recognition sites in rat brain cortical membranes. Among the divalent metal cations tested, Cd2+, Zn2+ and Cu2+ inhibited the specific 3H-GR 65630 binding activity to 5-HT3 receptors at a concentration of 0.1-1 mM. The other divalent metal cations tested (i.e. Co2+, Ni2+, Ba2+, Ca2+, Mg2+ and Mn2+) produced no inhibition of the specific 3H-GR 65630 binding. Cd2+, Zn2+ and Cu2+ did not change the Bmax value of the binding activity, but significantly increased the Kd value. It was suggested that these cations inhibited the binding activity by reducing affinity of the 5-HT3 receptor for the antagonist, resulting in apparent inhibition of the binding activity. As to the binding association rate, Cd2+, Cu2+ and Zn2+ were found to have an inhibitory effect. The binding dissociation rate, however, was shown to be decreased by Cu2+ but not by Cd2+ and Zn2+. Furthermore, the Zn(2+)-induced inhibition of 3H-GR 65630 binding was suggested to be antagonized by both concanavalin A and wheatgerm agglutinin. The Cu(2+)-induced inhibition, however, was not influenced by these lectins, indicating that Cu2+ has a different lectin sensitivity for its inhibitory effect. The different mechanism of action between Cu2+ and Zn2+ was suggested in their inhibitory effect on the specific 3H-GR 65630 binding activity.
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PMID:Differential effects of divalent cations on specific 3H-GR 65630 binding to 5-HT3 receptors in rat cortical membranes. 802 34

The emetic effects of copper sulfate and cisplatin and the potential involvement of vagal afferent fibers and 5-HT3 receptors in the emesis were investigated in cynomolgus monkeys. Retching and vomiting induced by both oral (100 mg/kg) and intravenous (20 mg/kg) copper sulfate were inhibited markedly by abdominal vagotomy. Furthermore, the emetic response induced by oral copper sulfate was strongly inhibited by intravenous ICS 205-930 (0.1 mg/kg), a 5-HT3 receptor antagonist. Cisplatin (3 mg/kg, i.v.) caused severe retching and vomiting, and the number of emetic responses was much greater than that in other species. The emetic response induced by cisplatin was inhibited markedly by abdominal vagotomy or concurrent administration of ICS 205-930 (3 x 0.1 mg/kg, i.v.). These results suggest that the monkey is more sensitive to cisplatin than other species and that the vagal afferent terminals and 5-HT3 receptors play an important role in the emetic response induced by copper sulfate and cisplatin.
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PMID:Involvement of 5-HT3 receptors and vagal afferents in copper sulfate- and cisplatin-induced emesis in monkeys. 828 15

In Suncus murinus, various emetic responses and the anti-emetic activity of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128 (2-[(2-methylimidazol-1-yl) methyl benzo[f]thiochromen-1-one monohydrochloride hemihydrate), were investigated. Cancer chemotherapeutic agents, cisplatin and cyclophosphamide, dose-dependently induced emesis of long-lasting duration. The 5-HT3 receptor agonist, 2-methyl-5-HT, and copper sulfate also induced emesis of short duration. However, another 5-HT3 receptor agonist, m-chlorophenylbiguanide, was not consistently emetic. GK-128 inhibited the emetic responses induced by chemotherapeutic agents and 2-methyl-5-HT with similar potency. The anti-emetic action of GK-128 was more potent than that of ondansetron, Y-25130, granisetron and metoclopramide. The order of potency of these drugs, except granisetron, was consistent with that of their 5-HT3 receptor binding affinity in rat cortex. GK-128 failed to inhibit copper sulfate-induced emesis. These data suggest that GK-128 has a potent inhibitory effect on emesis via the 5-HT3 receptor, and that the 5-HT3 receptor involved in emesis in Suncus murinus may be different from the classically defined 5-HT3 receptor in other animals such as rats, dogs and ferrets.
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PMID:The anti-emetic activity of GK-128 in Suncus murinus. 884 9

In order to elucidate possible male/female differences in emesis, the effects of various emetogenic drugs (cisplatin, copper sulfate, veratrine, nicotine, serotonin) and motion stimulus were compared between male and female Suncus murinus. Cisplatin (IP), nicotine (SC), veratrine (SC) and copper sulfate (PO) induced dose-dependent emesis in either sex, and there was no apparent difference in estimated ED50 values. However, male animals tended to be more susceptible to serotonin-induced emesis. The ID50 values for tropisetron, a 5-HT3 receptor antagonist, to block serotonin-induced emesis were also similar between male and female animals. However, tropisetron was less effective against cisplatin-induced emesis in females. Therefore, cisplatin may release more serotonin to induce emesis in females. Reciprocal shaking (horizontal oscillation 40 mm, frequency 0.5 to 2.0 Hz, duration 5 min) induced more frequent emesis in male animals, and the latency to the first vomit was shorter in males than in females. These results suggest that there is substantial sex-dependent difference in the emetic responses and male animals are in general more susceptible. These results are discussed in the light of similar studies in man.
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PMID:Male/female differences in drug-induced emesis and motion sickness in Suncus murinus. 925 99


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