5-HT3 receptor( Ki = 5.3 nM ); α7 nAChR ( Ki = 6.9 nM )

In vitro activity: Tropisetron prevents human peripheral T cell proliferation and IL-2 production in response to antigens. Tropisetron suppresses the signaling cascades that govern the transcription factors NFAT, NF-κB, and AP-1 activation, all of which are known to be essential for the immune response[2].

In vitro activity: Tropisetron binds with great affinity to both 5HT3R and th α7 nAChR. With respect to the other nicotinic subtypes tested, tropisetron has very little affinity. [1] With antiemetic properties, tropisetron is a potent and selective antagonist of the serotonin 3 (5-hydroxytryptamine; 5-HT3) receptor. Its action is likely mediated by antagonistic interactions with receptors in the central nervous system as well as peripheral locations. [2] A strong inhibitor of both early and late phases of TCR-mediated T cell activation is tropisetron. In stimulated T cells, tropisetron selectively inhibits IL-2 gene transcription as well as IL-2 synthesis. Ttropisetron inhibits NFAT and AP-1 transcriptional activity as well as their ability to bind to DNA. Tropisetron is a strong antagonist that inhibits the activation of NF-(kappa)B induced by PMA plus ionomycin, but it has no effect on NF-(kappa)B mediated by TNF(alpha). [3] In isolated pig retinal ganglion cells (RGCs), tropisetron acts on α7 nAChRs to provide neuroprotection against glutamate-induced excitotoxicity. Tropisetron inhibits apoptosis by lowering the levels of p38MAP kinase. Applying tropisetron to cultures an hour before glutamate application can protect retinal ganglion cells (RGCs) from a glutamate assault in a dose-dependent manner. [4]

Tropisetron (1 mg/kg i.p.) dramatically improves the impaired inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice.[5]

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Tropisetron is a potent and selective serotonin 3 (5-hydroxytryptamine3; 5-HT3) receptor antagonist with antiemetic properties, probably mediated via antagonism of receptors both at peripheral sites and in the central nervous system. When compared with antiemetic regimens containing high-dose metoclopramide in a small number of studies, tropisetron was generally as effective at preventing acute and delayed vomiting induced by high-dose cisplatin (> or = 50 mg/m2). In these studies tropisetron completely prevented vomiting occurring in the first 24 hours after chemotherapy in 35 to 76% of patients. Tropisetron was superior to alizapride in preventing emesis induced by high-dose alkylating agents. The effectiveness of tropisetron in patients who had previously had partial control of emesis was improved by the addition of dexamethasone. Tropisetron appears to be well tolerated with the most frequently reported adverse effect being headache. Extrapyramidal effects, which can occur in 5 to 10% of patients receiving high-dose metoclopramide and which may limit its use, have been reported in only isolated cases with tropisetron. Thus, tropisetron is an effective, apparently well tolerated agent which can be administered once daily for the prevention of chemotherapy-induced nausea and vomiting. However, further clinical experience is needed to clarify the optimum role of tropisetron as an antiemetic agent, particularly with regard to other drugs in its class. Nonetheless, preliminary results indicate that tropisetron will be a useful alternative for use in controlling emesis induced by cytotoxic therapy. [2]

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Administration of tropisetron (1 mg/kg i.p.) significantly improved the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice. Coadministration of methyllycaconitine (MLA; 3 mg/kg i.p.), a partially selective antagonist at alpha 7 nicotinic receptors, significantly blocked the normalizing effect of tropisetron. Furthermore, MLA alone did not alter the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice. Conclusions: The data suggest that tropisetron improves the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice by effects on alpha 7 and perhaps alpha 4 beta 2 nicotinic receptors. Tropisetron may be useful for the treatment of deficient inhibitory processing in schizophrenia [5].

Tropisetron may lessen the effects of ischemic brain injury by lowering TNF-α and myeloperoxidase activity. In an experimental model of cisplatin-induced nephrotoxicity, tropisetron produces anti-inflammatory effects that are entirely independent of 5-HT3 receptors[3].

The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors. [1]

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Tropisetron, an antagonist of serotonin type 3 receptor, has been investigated in chronic inflammatory joint process. Since T cells play a key role in the onset of several inflammatory diseases, we have evaluated the immunosuppressive activity of tropisetron in human T cells, discovering that this compound is a potent inhibitor of early and late events in TCR-mediated T cell activation. Moreover, we found that tropisetron specifically inhibited both IL-2 gene transcription and IL-2 synthesis in stimulated T cells. To further characterize the inhibitory mechanisms of tropisetron at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-(kappa)B, NFAT and AP-1 transcription factors in Jurkat T cells. We found that tropisetron inhibited both the binding to DNA and the transcriptional activity of NFAT and AP-1. We also observed that tropisetron is a potent inhibitor of PMA plus ionomycin-induced NF-(kappa)B activation but in contrast TNF(alpha)-mediated NF-(kappa)B activation was not affected by this antagonist. Finally, overexpression of a constitutively active form of calcineurin indicated that this phosphatase may represent one of the main targets for the inhibitory activity of tropisetron. These findings provide new mechanistic insights into the anti-inflammatory activities of tropisetron, which are probably independent of serotonin receptor signalling and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases [3].

In either case, p65, JNK, ERK1 + 2, p38, and IκBα proteins were stimulated in Jurkat cells (1 × 10⁶ cells/ml) using TNFα (2 ng/ml) or PMA (20 ng/ml) plus ionomycin (0.5 ug/ml) in the presence or absence of tropisetron. Following a PBS wash, proteins were extracted using 50 μl of lysis buffer that contained 0.5% NP-40. The Bradford assay was used to determine the protein concentration. After boiling 30 μg of proteins in Laemmli buffer, the proteins were electrophoresed in 10% SDS/polyacrylamide gels.

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Cell survival was increased to an average of 105% in retinal ganglion cells (RGCs) pretreated with 100 nM tropisetron before glutamate, in comparison to controls. Tropisetron is thought to be an efficient neuroprotective agent against glutamate-induced excitotoxicity, as it is mediated by α7 nAChR activation, according to inhibition studies conducted with the alpha7 nAChR antagonist MLA (10 nM2). p38 MAPK levels linked to excitotoxicity were dramatically reduced by tropisetron from an average of 15 ng/ml to 6 ng/ml, while pAkt levels were not affected in any appreciable way. Tropisetron over-expresses the CB(1) receptors at both transcriptional and protein levels, inhibits the phosphatase activity of calcineurin significantly (but not granisetron), and lowers the amount of cAMP in cerebellar granule neurons.

Male albino mice
3 mg/kg
i.p.

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The ratio of the amplitudes of response to the second (test) stimulus and the first (conditioning) stimulus provides a measure of sensory inhibition; the ratio of the test to the conditioning amplitude (TC ratio) is 0.5 or less for most rodent strains and normal humans (Stevens et al. 1996). Four records were obtained before any drug injection to establish baseline sensory processing performance. Each mouse was drug naive at the time of experimentation. To determine the optimal agonist dose of tropisetron, we examined several doses in a preliminary experiment (0.3, 1, and 3 mg/kg). The 1- and 3-mg/kg doses improved the inhibition of P20–N40 responses in DBA/2 mice. Therefore, the lowest effective dose (1 mg/kg) was selected for further study in comparison with saline vehicle in groups of eight mice. In a subsequent group of studies, the antagonist MLA was administered peripherally (3 mg/kg in saline i.p.), a dose that results in brain levels adequate to antagonize α7 nicotinic receptors (Turek et al. 1995). Recordings were obtained at 5-min intervals for 20 min before and 60 min after injection of each substance. [5]

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Absorption, Distribution and Excretion
The absorption of tropisetron from the gastrointestinal tract is rapid (mean half-life of about 20 minutes) and nearly complete (more than 95%). Due to first-pass metabolism in the liver, the absolute bioavailability of a 5 mg oral dose is 60%. The peak plasma concentration is attained within three hours.
About 8% of tropisetron is excreted in the urine as unchanged drug, 70% as metabolites; 15% is excreted in the feces.
400-600 L.
1800 ml/min.

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Metabolism / Metabolites
The metabolism of tropisetron occurs by hydroxylation at the 5, 6 or 7 positions of its indole ring, followed by a conjugation reaction to the glucuronide or sulphate with excretion in the urine or bile (urine to faeces ratio 5:1). The metabolites have a greatly reduced potency for the 5-HT3 receptor and do not contribute to the pharmacological action of the drug.
Tropisetron has known human metabolites that include 8-Azabicyclo[3.2.1]octan-3-yl 1H-indole-3-carboxylate, (8-methyl-8-azabicyclo[3.2.1]octan-3-yl) 5-hydroxy-1H-indole-3-carboxylate, and (8-methyl-8-azabicyclo[3.2.1]octan-3-yl) 6-hydroxy-1H-indole-3-carboxylate.

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Biological Half-Life
5.7 h.

Protein Binding
71% bound to plasma protein in a non-specific manner.

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rat LD50 oral 265 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly., 40(2445), 1998
rat LD50 intravenous 31400 ug/kg Gekkan Yakuji. Pharmaceuticals Monthly., 40(2445), 1998
mouse LD50 oral 487 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly., 40(2445), 1998
mouse LD50 intravenous 37900 ug/kg Gekkan Yakuji. Pharmaceuticals Monthly., 40(2445), 1998

[1]. Bioorg Med Chem Lett. 2001 Feb 12;11(3):319-21.

[2]. Drugs. 1993 Nov;46(5):925-43.

[3]. Biochem Pharmacol. 2005 Aug 1;70(3):369-80.

[4]. Neuropharmacology. 2013 Oct:73:111-21.

[5]. Psychopharmacology (Berl). 2005 Nov;183(1):13-9.

Tropisetron is an indolyl carboxylate ester obtained by formal condensation of the carboxy group of indole-3-carboxylic acid with the hydroxy group of tropine. It has a role as a serotonergic antagonist, an antiemetic, a nicotinic acetylcholine receptor agonist, a trypanocidal drug, an immunomodulator, a neuroprotective agent, an apoptosis inhibitor and an anti-inflammatory agent. It is an indolyl carboxylate ester, an azabicycloalkane and a tertiary amino compound. It is functionally related to an indole-3-carboxylic acid and a tropine. It is a conjugate base of a tropisetron(1+).
Tropisetron is an indole derivative with antiemetic activity. As a selective serotonin receptor antagonist, tropisetron competitively blocks the action of serotonin at 5HT3 receptors, resulting in suppression of chemotherapy- and radiotherapy-induced nausea and vomiting. Tropisetron appears to be well tolerated with the most frequently reported adverse effect being headache. Extrapyramidal side effects are rare upon using tropisetron.
Tropisetron is an indole derivative with antiemetic activity. As a selective serotonin receptor antagonist, tropisetron competitively blocks the action of serotonin at 5HT3 receptors, resulting in suppression of chemotherapy-and radiotherapy-induced nausea and vomiting. (NCI04)
An indole derivative and 5-HT3 RECEPTOR antagonist that is used for the prevention of nausea and vomiting.

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Drug Indication
For the prevention of nausea and vomiting induced by cytotoxic therapy and postoperative.

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Mechanism of Action
Tropisetron competitively binds to and blocks the action of serotonin at 5HT3 receptors peripherally on vagus nerve terminals located in the gastrointestinal (GI) tract as well as centrally in the chemoreceptor trigger zone (CTZ) of the area postrema of the central nervous system (CNS). This results in the suppression of chemotherapy- and radiotherapy-induced nausea and vomiting.

C17H20N2O2

284.3529

284.15

C, 71.81; H, 7.09; N, 9.85; O, 11.25

89565-68-4

Tropisetron Hydrochloride; 105826-92-4

656665

White to light yellow solid powder

1.3±0.1 g/cm3

448.5±35.0 °C at 760 mmHg

201-202 °C

225.0±25.9 °C

0.0±1.1 mmHg at 25°C

1.644

3.55

1

3

3

21

400

2

C(C1=CNC2C=CC=CC1=2)(=O)O[C@@H]1C[C@@H]2CC[C@@H](N2C)C1

ZNRGQMMCGHDTEI-FUNVUKJBSA-N

InChI=1S/C17H20N2O2/c1-19-11-6-7-12(19)9-13(8-11)21-17(20)15-10-18-16-5-3-2-4-14(15)16/h2-5,10-13,18H,6-9H2,1H3/t11-,12+,13?

[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 1H-indole-3-carboxylate

ICS 205930; 89565-68-4; Tropisetronum; [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 1H-indole-3-carboxylate; Novaban; Navoban; Tropisteron; ICS 205930; ICF 205-930; Tropisetron

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~10 mg/mL (~35.2 mM)
Water: ~56 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)