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 serotonin (5-hydroxytryptamine, 5-HT) antagonists, which bind at the type 3 receptor (5-HT3 receptor), have been evaluated in several preclinical models and found to be effective in alleviating cancer therapy-related emesis. The antiemetic efficacy of ondansetron (GRF-38032F, odanserin), granisetron (BRL-43694), tropisetron (ICS-205930), MDL-72222 and MDL-73147EF, batanopride (BMY-25801-01) and several others is at various stages of investigation. Ondansetron is currently marketed in several countries and the same will soon be true for granisetron. At this stage it is not yet possible to evaluate the comparative efficacy of each of these compounds, although recent preclinical data reveal some differences in the affinity of these compounds, for other receptors. Side effects related to these agents have been minor, consisting mainly of slight headaches; possible rises in liver enzymes related to some compounds need further evaluation. Future studies will need to determine the exact role of 5-HT3 antagonists, although their cost may confine their use to patients at high risk for side effects from metoclopramide.
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PMID:5-HT3 receptor antagonists. An overview of their present status and future potential in cancer therapy-induced emesis. 172 61

The emetic effects of 5-hydroxytryptamine (5-HT) and 5-HT3 receptor agonists were investigated in the house musk shrew, Suncus murinus. 5-Hydroxytryptamine (5-HT; i.p., i.v., s.c.) and 2-methyl-5-HT (2-Me-5-HT; i.p.) but not 5-hydroxyindoleacetic acid (i.p.) or 5-methoxytryptamine (i.p.) induced emesis with very short latency. Tropisetron (ICS 205-930, a 5-HT3 receptor antagonist, s.c.) blocked the emesis induced by 5-HT (10 mg/kg, i.p.) and 2-Me-5-HT (5 mg/kg, i.p.) with respective ID50 values of 7.8 and 70.9 micrograms/kg. Pindolol (5-HT1 receptor antagonist) and ketanserin (5-HT2 receptor antagonist) were about 100 times less potent than tropisetron. The emesis induced by 5-HT was prevented by surgical vagotomy but not by pretreatment with a combination of atropine (0.1 mg/kg, s.c.) and hexamethonium (10 mg/kg, s.c.). These results clearly indicate that 5-HT is emetogenic probably through a stimulation of peripheral 5-HT3 receptors.
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PMID:5-Hydroxytryptamine is emetogenic in the house musk shrew, Suncus murinus. 172 7

Experimental evidence suggests an important role of serotonin in the process of learning and memory. The present study investigated the effect of 5HT3-receptor antagonist (ICS 205-930) on retrieval of a previously learned aversive habit in the mouse. The effect of ICS 205-930 on scopolamine (3 mg/kg) induced amnesia was also studied. ICS 205-930 (1, 10 & 100 micrograms/kg) produced a dose-dependent increase in latency to cross into the dark chamber. The scopolamine induced memory impairment was significantly attenuated by ICS 205-930 (10 micrograms/kg). These results suggest that memory deficits may be susceptible to attenuation with non-cholinergic treatments.
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PMID:Enhancement of memory retrieval and attenuation of scopolamine-induced amnesia following administration of 5-HT3 antagonist ICS 205-930. 177 28

The ability of selective 5-HT3 receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT3 receptor antagonists that are substituted tropines, ICS 205-930 (0.1-0.56 mg/kg) and MDL 72222 (3.0-17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT3 receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25-40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56-1.7 mg/kg), which is also a 5-HT3 receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT2 receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT3 mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT3 receptor antagonists influence their ability to block this action of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists. 178 Apr 14

The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (-log IC50 9.30-11.9 and 6.8-8.20, in heart and ileum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID50 ranging from 3.7 to 147 micrograms/kg). All agents accelerated gastric emptying of solids in rats (ED50 about 10-160 micrograms/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.
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PMID:Pharmacological properties of a novel class of 5-HT3 receptor antagonists. 180 Jan 17

1. The biochemical and pharmacological properties of 5-HT3 receptors in homogenates of NG108-15 and NCB-20 neuroblastoma cells and rat cerebral cortex have been ascertained by the use of [3H]-quipazine and [3H]-GR65630 binding. 2. In NG108-15 and NCB-20 cell homogenates, [3H]-quipazine bound to a single class of high affinity (NG108-15: Kd = 6.2 +/- 1.1 nM, n = 4; NCB-20: Kd = 3.0 +/- 0.9 nM, n = 4; means +/- s.e.means) saturable (NG108-15: Bmax = 1340 +/- 220 fmol mg-1 protein; NCB-20: Bmax = 2300 +/- 200 fmol mg-1 protein) binding sites. In rat cortical homogenates, [3H]-quipazine bound to two populations of binding sites in the absence of the 5-hydroxytryptamine (5-HT) uptake inhibitor, paroxetine (Kd1 = 1.6 +/- 0.5 nM, Bmax1 = 75 +/- 14 fmol mg-1 protein; Kd2 = 500 +/- 300 nM, Bmax2 = 1840 +/- 1040 fmol mg-1 protein, n = 3), and to a single class of high affinity binding sites (Kd = 2.0 +/- 0.5 nM, n = 3; Bmax = 73 +/- 6 fmol mg-1 protein) in the presence of paroxetine. The high affinity (nanomolar) component probably represented 5-HT3 binding sites and the low affinity component represented 5-HT uptake sites. 3. [3H]-paroxetine bound with high affinity (Kd = 0.02 +/- 0.003 nM, n = 3) to a site in rat cortical homogenates in a saturable (Bmax = 323 +/- 45 fmol mg-1 protein, n = 3) and reversible manner. Binding to this site was potently inhibited by 5-HT uptake blockers such as paroxetine and fluoxetine (pKi s = 8.6-9.9), while 5-HT3 receptor ligands exhibited only low affinity (pK; < 7). No detectable specific [3H]-paroxetine binding was observed in NG108-15 or NCB-20 cell homogenates. 4. [3H]-quipazine binding to homogenates of NG108-15, NCB-20 cells and rat cortex (in the presence of 0.1 microM paroxetine) exhibited similar pharmacological characteristics. 5-HT3 receptor antagonists competed for [3H]-quipazine binding with high nanomolar affinities in the three preparations and the rank order of affinity was: (S)-zacopride > quarternized ICS 205-930 2 granisetron > ondansetron > ICS 205-209 (R)-zacopride > quipazine > renzapride > MDL-72222 > butanopride > metoclopramide. 5. [3H]-GR65630 labelled a site in NCB-20 cell homogenates with an affinity (Kd = 0.7 + 0.1 nms n = 4) and density (B__ = 1800 + 1000 fmol mg- protein) comparable to that observed with [3H]-quipazine. Competition studies also indicated a good correlation between the pharmacology of 5-HT3 binding sites when [3H]-GR65630 and [3H]-quipazine were used in these cells. 6. In conclusion, [3H]-quipazine labelled 5-HT3 receptor sites in homogenates of NG108-15 cells, NCB-20 cells and rat cerebral cortex. In rat cortical homogenates, [3H]-quipazine also bound to 5-HT uptake sites, which could be blocked by 0.1 microM paroxetine. The pharmacological specificity of the 5-HT3 receptor labelled by [3H]-quipazine was similar in the neuroblastoma cells and rat cortex and was substantiated in NCB-20 cells by the binding profile of the selective 5-HT3 receptor antagonist, [3H]-GR65630.
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PMID:Characteristics of 5-HT3 binding sites in NG108-15, NCB-20 neuroblastoma cells and rat cerebral cortex using [3H]-quipazine and [3H]-GR65630 binding. 183 Feb 36

The novel, naphthylpiperazine 5-HT1A agonist, S 14671 (4-[(thenoyl-2)aminoethyl]-1-(7-methoxynaphtylpiperazine], displayed very high affinity for 5-HT1A binding sites (pKi = 9.3) as compared to the serotonin (5-HT)1A agonists, 8-OH-DPAT (9.2) and (+)-flesinoxan (8.7) and the 5-HT1A partial agonists, buspirone (7.9) and BMY 7378 (8.8). In vivo, S 14671 induced the typical 5-HT1A agonist-induced responses of hypothermia and spontaneous tail-flicks at doses as low as greater than or equal to 5 micrograms/kg s.c. and greater than or equal to 40 micrograms/kg s.c., respectively. In each test, it was about 10-fold more potent than 8-OH-DPAT and 100-fold more potent than (+)-flesinoxan and buspirone. The actions of S 14671 could be blocked by BMY 7378 and the 5-HT1A receptor antagonist, (-)-alprenolol, but not by the 5-HT1C/2 receptor antagonist, ritanserin, nor the 5-HT3 receptor antagonist, ICS 205930. Thus, S 14671 is a novel 5-HT1A ligand of high efficacy and exceptional in vivo potency.
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PMID:S 14671: a novel naphthylpiperazine 5-HT1A agonist of high efficacy and exceptional in vivo potency. 183 84

In the present experiments we have investigated the possible coupling of 5-hydroxytryptamine (HT)3 receptors to the metabolism of phosphatidylinositol (PI) in the rat fronto-cingulate and entorhinal cortices, two brain regions with relatively high density of this receptor subtype. 5-HT dose-dependently increases PI turnover (20-80% increase above basal stimulation), with an EC50 of 0.5 and 0.3 microM for fronto-cingulate and entorhinal cortices, respectively. This effect was blocked by the selective 5-HT3 antagonists, BRL 43694 (granisetron), GR 38032F (ondansetron) and ICS 205-930. The selective 5-HT3 receptor agonists, 2-methyl-serotonin (2-Me-5-HT) and phenylbiguanide (PBG), mimicked the action of 5-HT and dose-dependently produced a significant increase in PI turnover (46-76% of the 5-HT response). The stimulatory action of 2-Me-5-HT and phenylbiguanide was blocked completely by granisetron, ondansetron and ICS 205-930 but not by other receptor antagonists such as (+/-)-pindolol (a beta, 5-HT1A and 5-HT1B receptor antagonist), methy-sergide (a 5-HT1 and 5-HT2 receptor antagonist), ritanserin (a 5-HT1C and 5-HT2 receptor antagonist), SR 95103 (gamma-aminobutyric acidA receptor antagonist), scopolamine (a muscarinic antagonist), (-)-eticlopride (a D2 receptor antagonist), SCH 23390 (a D1 5-HT2/1C receptor antagonist) and prazosin (an alpha-1 receptor antagonist). In addition, the stimulation of PI turnover by 2-Me-5-HT was antagonized stereospecifically by the 5-HT3 receptor blocker zacopride. Thus, only the active enantiomer (S)-zacopride, but not the less active enantiomer (R)-zacopride, was effective in blocking the 2-Me-5-HT-induced effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of 5-hydroxytryptamine3 receptor agonists on phosphoinositides hydrolysis in the rat fronto-cingulate and entorhinal cortices. 184 25

1. The effects of 5-hydroxytryptamine (5-HT) and of the 5-HT1-like receptor agonists, 5-carboxamidotryptamine (5-CT) and sumatriptan (GR43175) were investigated in isolated ring preparations of guinea-pig common iliac artery. 2. The three agonists induced very weak, if any, contractions of unstimulated preparations, whereas they elicited concentration-dependent contractions in preparations given a moderate tone by a threshold concentration of prostaglandin F2 alpha (PGF2 alpha). 3. Under the latter conditions, Emax values for 5-HT and 5-CT reached about 45% of PGF2 alpha maximal effect, whereas the Emax value of sumatriptan was significantly lower (about 35%). The rank order of potency (mean EC50 value, nM) was 5-CT (6.6) greater than 5-HT (22.9) greater than sumatriptan (155). Pargyline, cocaine or deoxycorticosterone were without significant effect on the contractions induced by 5-HT. 4. The 5-HT3 receptor antagonist, (1 alpha H, 3 alpha,5 alpha H-tropan-3-yl) 1-H-indole-3-carboxylic acid ester (ICS 205-930; 1 microM), had no effect on 5-HT-, 5-CT- and sumatriptan-induced contractions. 5. The 5-HT2 receptor antagonist, ketanserin (1 microM) caused only small rightward shifts (concentration-ratios, about 2) in the concentration-response curves to 5-HT, 5-CT and sumatriptan without significantly depressing the maximum effects. 6. In the presence of ketanserin (1 microM), the non-selective 5-HT receptor antagonist, methiothepin (0.1 microM), shifted the concentration-response curves to 5-HT and 5-CT to the right in a parallel manner and to a similar extent for both agonists (respective mean pKB values, 8.07 and 8.27). The effect of sumatriptan was also antagonized by methiothepin, but solvent effects precluded quantitative analysis of this antagonism. 7. It is concluded that 5-HT1-like receptors mediate the contractions induced by 5-HT, 5-CT and sumatriptan in guinea-pig isolated iliac artery. For reasons not yet understood, these receptors are detected only when the tissues are moderately pre-contracted by PGF2alpha.
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PMID:5-HT1-like receptors mediate 5-hydroxytryptamine-induced contraction of guinea-pig isolated iliac artery. 184 68

1. An investigation has been made into the 5-hydroxytryptamine (5-HT) receptor mediating relaxation of rat oesophagus in preparations precontracted with carbachol. 2. In tissues treated with pargyline (100 microM) and in the presence of corticosterone (30 microM) and cocaine (30 microM) the potency of 5-HT and 5-methoxytyramine (5-MeOT) was not changed but the maximum response to these agonists was reduced. Thus there was no evidence of metabolism and/or uptake through an amine depleting mechanism. 3. The relaxant concentration-effect curves to 5-HT were shifted to the left in a concentration-related manner by isobutylmethylxanthine (1 and 10 microM), suggesting the involvement of adenosine 3':5'-cyclic monophosphate in these responses. 4. 5-HT produced concentration-related relaxations of rat oesophagus with an EC50 value of 0.24 microM. Several indole agonists were tested and the following rank order of potency of key agonists obtained: 5-HT greater than alpha-methyl-5-hydroxytryptamine = 5-carboxamidotryptamine (5-CT) greater than 5-MeOT. In contrast, 2-methyl-5-hydroxytryptamine, sumatriptan and 8-hydroxy-2-(di-n-propylamino) tetralin were weak or inactive. 5. The substituted benzamides, metoclopramide, cisapride, renzapride and R,S-zacopride acted as partial agonists, producing 60-70% of the 5-HT maximum. 6. The relaxation responses to 5-HT were neither inhibited by antagonists selective for 5-HT1 or 5-HT2 receptors nor by the 5-HT3 receptor antagonists, ondansetron, granisetron or MDL 72222. 7. The relaxation responses induced by 5-HT, 5-CT, 5-MeOT and renzapride were selectively inhibited by high concentrations of ICS 205-930 with pKB values of approximately 6. 8. The 5-HT receptor mediating relaxation in rat oesophagus cannot be designated 5-HT1, 5-HT2 or 5-HT3 under the current 5-HT classification, but the observed effects are consistent with stimulation of the putative 5-HT4 receptor.
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PMID:Investigation into the 5-hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus. 187 46


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