5-HT₃ Receptor ( IC50 = 70.1 nM )

体外活性：托烷司琼是 α7 nAChR 和 5HT3R 的高亲和力配体。托烷司琼对所测试的其他烟碱亚型的亲和力非常低。托烷司琼是一种有效的选择性血清素 3 (5-羟色胺3; 5-HT3) 受体拮抗剂，具有止吐特性，可能通过拮抗外周部位和中枢神经系统的受体来介导。托烷司琼是 TCR 介导的 T 细胞激活早期和晚期事件的有效抑制剂。 Tropisetron 特异性抑制受刺激 T 细胞中的 IL-2 基因转录和 IL-2 合成。 Ttropisetron 抑制 NFAT 和 AP-1 与 DNA 的结合以及转录活性。托烷司琼是 PMA 加离子霉素诱导的 NF-(kappa)B 激活的有效抑制剂，但相比之下，TNF(α) 介导的 NF-(kappa)B 激活不受该拮抗剂的影响。托烷司琼作用于离体猪视网膜神经节细胞 (RGC) 上的 α7 nAChR，提供针对谷氨酸诱导的兴奋性毒性的神经保护作用。托烷司琼可降低 p38MAP 激酶水平，从而抑制细胞凋亡。当在谷氨酸施用前 1 小时应用于培养物时，托烷司琼能够以剂量依赖的方式保护视网膜神经节细胞 (RGC) 免受谷氨酸攻击。细胞测定：与对照相比，在谷氨酸之前用 100 nM 托烷司琼预处理的视网膜神经节细胞 (RGC) 使细胞存活率平均提高了 105%。使用 α7 nAChR 拮抗剂 MLA (10 nM) 进行的抑制研究支持托烷司琼是针对谷氨酸诱导的兴奋性毒性的有效神经保护剂的假设；由 α7 nAChR 激活介导。托烷司琼对 pAkt 水平没有明显影响，但显着降低与兴奋性毒性相关的 p38 MAPK 水平，从平均 15 ng/ml 降至 6 ng/ml。托烷司琼（而非格拉司琼）显着抑制钙调神经磷酸酶的磷酸酶活性，在转录和蛋白质水平上过度表达 CB(1) 受体，并降低小脑颗粒神经元 (CGN) 中的 cAMP 含量。

Tropisetron (1 mg/kg ip) 显着改善 DBA/2 小鼠 P20-N40 听觉诱发电位的抑制处理缺陷。

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托烷司琼是一种强效且选择性的血清素3（5-羟色胺3；5-HT3）受体拮抗剂，具有止吐特性，可能是通过拮抗外周部位和中枢神经系统的受体介导的。在少数研究中，与含有高剂量胃复安的止吐方案相比，托烷司琼在预防高剂量顺铂（≥50mg/m2）引起的急性和延迟呕吐方面通常同样有效。在这些研究中，托烷司琼完全防止了35%至76%的患者在化疗后24小时内出现呕吐。托烷司琼在预防大剂量烷化剂引起的呕吐方面优于茜素必利。通过添加地塞米松，托烷司琼对以前部分控制呕吐的患者的疗效得到了改善。托烷司琼似乎耐受良好，最常见的不良反应是头痛。锥体外系效应可能发生在接受高剂量胃复安治疗的5%至10%的患者中，这可能会限制其使用，但只有托烷司琼的孤立病例报告了这种效应。因此，托烷司琼是一种有效、耐受性良好的药物，可以每天服用一次，用于预防化疗引起的恶心和呕吐。然而，需要进一步的临床经验来阐明托烷司琼作为止吐剂的最佳作用，特别是与同类其他药物相比。尽管如此，初步结果表明，托烷司琼将是控制细胞毒性治疗引起的呕吐的有用替代品。[2]

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托烷司琼（1mg/kg i.p.）的给药显著改善了DBA/2小鼠P20-N40听觉诱发电位的抑制处理缺陷。甲基乌头碱（MLA；3mg/kg i.p.）是α7烟碱受体的部分选择性拮抗剂，与之联合给药可显著阻断托烷司琼的正常化作用。此外，单独使用MLA不会改变DBA/2小鼠P20-N40听觉诱发电位的抑制处理缺陷。 结论：数据表明，托烷司琼通过影响α7和可能的α4β2烟碱受体，改善了DBA/2小鼠P20-N40听觉诱发电位的抑制加工缺陷。托烷司琼可用于治疗精神分裂症中抑制加工缺陷[5]。

5-羟色胺3受体拮抗剂tropisetron/托烷司琼（ICS 205-930）被发现是α7烟碱受体的强效选择性部分激动剂。发现另外两种5-HT3受体拮抗剂昂丹司琼和LY-278584对α7烟碱受体缺乏高亲和力。托烷司琼的奎宁环类似物（1和2）也被发现是α7烟碱受体的强效选择性部分激动剂。[1]

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托烷司琼是一种血清素3型受体拮抗剂，已被研究用于慢性炎症关节过程。由于T细胞在几种炎症性疾病的发病中起着关键作用，评估了托烷司琼在人类T细胞中的免疫抑制活性，发现该化合物是TCR介导的T细胞活化早期和晚期事件的强效抑制剂。此外，发现托烷司琼特异性抑制受刺激T细胞中IL-2基因转录和IL-2合成。为了在转录水平上进一步表征托烷司琼的抑制机制，我们检测了Jurkat T细胞中NF-（κ）B、NFAT和AP-1转录因子的DNA结合和转录活性。研究发现，托烷司琼抑制了NFAT和AP-1与DNA的结合以及转录活性。还观察到托烷司琼是PMA加离子霉素诱导的NF-（κ）B活化的强效抑制剂，但与此相反，TNF（α）介导的NF-。最后，钙调神经磷酸酶组成型活性形式的过表达表明，这种磷酸酶可能是托烷司琼抑制活性的主要靶标之一。这些发现为托烷司琼的抗炎活性提供了新的机制见解，这些活性可能独立于血清素受体信号传导，并突显了它们设计新的治疗策略来管理炎症性疾病的潜力[3]。

与对照组相比，在谷氨酸之前用 100 nM 托烷司琼预处理的视网膜神经节细胞 (RGC) 中，细胞存活率平均增加了 105%。根据使用 α7 nAChR 拮抗剂 MLA (10 nM2) 进行的抑制研究，托烷司琼被认为是对抗谷氨酸诱导的兴奋性毒性的有效神经保护剂，因为它是由 α7 nAChR 激活介导的。托烷司琼将与兴奋性毒性相关的 p38 MAPK 水平从平均 15 ng/ml 显着降低至 6 ng/ml，而 pAkt 水平未受到任何明显影响。托烷司琼在转录和蛋白质水平上过度表达 CB(1) 受体，显着抑制钙调神经磷酸酶的磷酸酶活性（但不是格拉司琼），并降低小脑颗粒神经元中 cAMP 的量

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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1 mg/kg i.p.

Mice

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.

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In conclusion, the present study suggests that tropisetron improves the deficient inhibitory processing of the P20–N40 auditory evoked potential in DBA/2 mice through α7, and perhaps α4β2, nicotinic receptors. Tropisetron (Koike et al. 2005) thus joins clozapine as a medication that increases the inhibitory processing of auditory evoked responses in humans (Nagamoto et al. 1996, 1999) and animals (Simosky et al. 2003), and the two medications appear to share a common end effect on nicotinic receptors, especially the α7 subtype. If the correlation between failure of sensory inhibition and neurophysiological measures of attentional dysfunction in schizophrenia (Cullum et al. 1993) reflects a common neurobiological mechanism, then 5-HT3 antagonists, such as tropisetron and ondansetron, may offer a treatment option for attentional problems, and perhaps cognitive difficulties, often experienced by schizophrenia patients.[5]

C17H21CLN2O2

320.81

320.129

C, 64.57; H, 6.92; Cl, 10.59; N, 8.37; O, 9.56

105826-92-4

Tropisetron; 89565-68-4

656665

White to off-white solid powder

448.5ºC at 760 mmHg

283-285ºC

225ºC

3.09E-08mmHg at 25°C

2.83

41.9

1

3

3

21

400

2

Cl[H].O(C(C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)=O)C1([H])C([H])([H])[C@]2([H])C([H])([H])C([H])([H])[C@]([H])(C1([H])[H])N2C([H])([H])[H]

XIEGSJAEZIGKSA-KOQCZNHOSA-N

InChI=1S/C17H20N2O2.ClH/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;1H/t11-,12+,13?;

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

ICS-205-930; Tropisetron; ICS-205930; 105826-92-4; Tropisetron hydrochloride; TROPISETRON HCl; Tropisetron monohydrochloride; Tropisetron (Hydrochloride); (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1H-indole-3-carboxylate hydrochloride; SDZ-ICS-930; [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 1H-indole-3-carboxylate;hydrochloride; ICS 205930; ICS205930; ICS 205-930; Tropisetron HCl; Brand name: Navoban

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

配方 1 中的溶解度: 120 mg/mL (374.05 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。