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Purity: ≥98%
Talnetant (formerly also known as SB 223412) is a potent and selective NK3 receptor antagonist with ki value of 1.4 nM (hNK-3-CHO); Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that Talnetant is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 microM. Talnetant has been shown in vitro to be a potent functional antagonist of the hNK-3 receptor (reversing senktide-induced contractions in isolated rabbit iris sphincter muscles and reversing NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor). In vivo, however, this compound has been shown to exhibit oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced behavioral responses in rabbits). Talnetant may be used as a pharmacological tool in animal models of disease to evaluate the pathophysiological and functional role of the NK-3 receptor and to determine the appropriate use of non-peptide NK-3 receptor antagonists for therapeutic purposes, according to the biological data gathered thus far.
| Targets |
Human neurokinin-3 (NK3) receptor (Ki = 1.4 nM, determined by radioligand binding assay) [1]
- Human NK1 receptor (Ki > 1000 nM, no significant binding) [1] - Human NK2 receptor (Ki > 1000 nM, no significant binding) [1] |
|---|---|
| ln Vitro |
Talnetant (SB 223412) (0.1–1 μM) has the ability to decrease the build-up of NKB-induced IP in human NK3 receptor-expressing U-2OS cells[3].
Acts as a highly selective non-peptide antagonist of the human NK3 receptor, with >700-fold selectivity over NK1 and NK2 receptors [1] - Inhibited NK3 receptor-mediated intracellular calcium mobilization in CHO cells expressing human NK3 receptor: EC50 = 3.7 nM [1] - Blocked senktide (NK3 agonist)-induced phosphatidylinositol turnover in NK3-expressing cells by ~90% at 10 nM Talnetant (SB 223412) [1] - Inhibited senktide-induced neuronal firing in rat hypothalamic slices: IC50 = 5 nM, without affecting NK1/NK2-mediated responses [3] - No significant activity against 50+ other G protein-coupled receptors, ion channels, or enzymes at concentrations up to 1 μM [1] |
| ln Vivo |
Talnetant (SB 223412) (0.5-2 mg/kg iv, 2min pretreatment) can inhibit the miosis caused by senktide (25µg, iv) in a dose-dependent manner with an ED50 of 0.44mg/kg in conscious rabbits[1].
Talnetant (SB 223412) (i.p., 1-100 mg/kg, 1 h) can decrease haloperidol-induced increases in dopamine levels in the vomeronasal nucleus of freely moving guinea pigs, significantly increase extracellular dopamine and norepinephrine in the medial prefrontal cortex, and significantly attenuate "wet dog wagging" behavior induced by senktide in a dose-dependent manner[3].
In ICR mice, oral administration of Talnetant (SB 223412) (1-30 mg/kg) dose-dependently inhibited senktide-induced (stereotyped behavior), with ED50 = 5 mg/kg; the inhibitory effect lasted for ~6 hours [3] - In Sprague-Dawley rats, intraperitoneal injection of 10 mg/kg Talnetant (SB 223412) reduced NK3 agonist-induced hyperlocomotion by ~75% compared to vehicle control [3] - In healthy human volunteers (n=12), oral administration of 100 mg Talnetant (SB 223412) once daily for 7 days increased rectal compliance by ~30% and reduced rectal sensory thresholds for discomfort by ~25% [2] - Attenuated senktide-induced increases in mean arterial pressure in anesthetized rats: 3 mg/kg intravenous dose reduced pressure elevation by ~60% [1] |
| Enzyme Assay |
Radioligand binding assay for NK3 receptor: Membrane preparations from CHO cells expressing human NK3, NK1, or NK2 receptors were incubated with [125I]-senktide (NK3-selective ligand) and various concentrations of Talnetant (SB 223412) (0.01-1000 nM) in binding buffer. After incubation at 25°C for 120 minutes, unbound ligand was removed by filtration. Radioactivity of the bound fraction was measured, and Ki values were calculated by competition binding analysis [1]
- Calcium mobilization assay: CHO cells expressing human NK3 receptor were loaded with a fluorescent calcium indicator and pre-treated with Talnetant (SB 223412) (0.01-100 nM) for 30 minutes. Senktide (100 nM) was added, and fluorescence intensity was measured to assess intracellular calcium release. EC50 values were determined based on the inhibition of calcium mobilization [1] |
| Cell Assay |
NK3 receptor-mediated phosphatidylinositol turnover assay: NK3-expressing CHO cells were labeled with [3H]-inositol and pre-treated with Talnetant (SB 223412) (0.1-100 nM) for 1 hour. Cells were stimulated with senktide (100 nM) for 60 minutes, and total inositol phosphates were extracted. Radioactivity was measured by liquid scintillation counting, and inhibition rates were calculated [1]
- Hypothalamic slice neuronal firing assay: Rat hypothalamic slices were prepared and maintained in oxygenated artificial cerebrospinal fluid. Talnetant (SB 223412) (0.1-100 nM) was added to the incubation medium, followed by senktide (1 μM). Extracellular recordings were performed to measure neuronal firing rate, and IC50 was determined based on firing inhibition [3] |
| Animal Protocol |
Male Dunkin-Hartley guinea pig
1, 3, 10, 30 or 100 mg/kg Intraperitoneal injection; 1 h Mouse senktide-induced stereotypy model: Female ICR mice (20-25 g) were randomly divided into vehicle and treatment groups. Talnetant (SB 223412) was suspended in 0.5% carboxymethylcellulose sodium and administered orally at 1, 10, or 30 mg/kg, or intraperitoneally at 3 mg/kg. Thirty minutes later, senktide (1 mg/kg) was injected intraperitoneally, and stereotyped behavior (repetitive head movements) was recorded for 30 minutes [3] - Rat hemodynamic response model: Anesthetized Sprague-Dawley rats (250-300 g) were instrumented for mean arterial pressure measurement. Talnetant (SB 223412) (1, 3, 10 mg/kg) was administered intravenously, followed by senktide (0.3 mg/kg) 15 minutes later. Pressure changes were recorded for 60 minutes post-senktide injection [1] |
| ADME/Pharmacokinetics |
Rat pharmacokinetics: After a single oral dose of 10 mg/kg, the oral bioavailability was approximately 35%; the peak plasma concentration (Cmax) at 1.5 hours after administration was 0.8 μg/mL [1]
- Plasma half-life (t1/2) = 2.8 hours (rat); 10 hours (human) [1, 2] - Volume of distribution (Vd) was approximately 1.2 L/kg (rat); distributed in brain tissue, the brain/plasma concentration ratio was approximately 0.7 2 hours after oral administration [1] - Human pharmacokinetics (healthy volunteers): After oral administration of 100 mg, Tmax was 2 hours; Cmax was 2.3 μg/mL; approximately 60% was metabolized in the liver via cytochrome P450 3A4; approximately 40% was excreted in the urine as metabolites [2] - Plasma protein binding = approximately 95% (human); approximately 92% (rat) [1, 2] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: At concentrations up to 10 μM, no significant toxicity was observed in CHO cells, human hepatocytes, or neurons [1]
- Acute toxicity: LD50 > 300 mg/kg (oral administration in rats); LD50 > 100 mg/kg (intraperitoneal injection in rats) [1] - Human clinical tolerability: Oral administration of 100 mg daily for 7 consecutive days was well tolerated; mild adverse reactions included headache (8%) and nausea (5%), with no significant changes in liver and kidney function or hematological parameters [2] - Subchronic toxicity: Oral administration of 30 mg/kg daily in rats for 28 consecutive days did not cause weight loss, organ damage, or behavioral abnormalities [1] |
| References |
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| Additional Infomation |
Tanetan (SB-223,412) is a neurokinin 3 receptor antagonist developed by GlaxoSmithKline. Its various functions are currently under investigation, primarily for the treatment of irritable bowel syndrome (IBS), and it is also being investigated as a potential antipsychotic for the treatment of schizophrenia.
Drug Indications Its use in the treatment of schizophrenia and schistopathic disorder, irritable bowel syndrome (IBS), and chronic obstructive pulmonary disease (COPD) is under investigation. Tanettan (SB 223412) is a novel, selective non-peptide neurokinin-3 (NK3) receptor antagonist belonging to the quinoline carboxamide class [1, 3]. - Its mechanism of action involves competitive binding to the NK3 receptor, thereby blocking the binding of the endogenous ligand neurokinin B (NKB). Inhibition of downstream signal transduction (calcium mobilization, phosphatidylinositol turnover) [1, 3] - Potential therapeutic applications include schizophrenia (based on preclinical models of psychosis) and functional gastrointestinal disorders (by modulating rectal sensory function) [2, 3] - Demonstrated favorable pharmacokinetic properties (oral bioavailability, brain penetration) and safety in preclinical and early clinical studies [1, 2] - Higher oral absorption and longer half-life compared to peptide NK3 antagonists, supporting once-daily administration in humans [1] |
| Molecular Formula |
C25H22N2O2
|
|---|---|
| Molecular Weight |
382.4544
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| Exact Mass |
382.168
|
| Elemental Analysis |
C, 78.51; H, 5.80; N, 7.32; O, 8.37
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| CAS # |
174636-32-9
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| Related CAS # |
Talnetant hydrochloride; 204519-66-4
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| PubChem CID |
5311424
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| Appearance |
White to off-white solid powder
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| Density |
1.212g/cm3
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| Boiling Point |
580.4ºC at 760mmHg
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| Flash Point |
304.8ºC
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| Vapour Pressure |
4.51E-14mmHg at 25°C
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| Index of Refraction |
1.657
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| LogP |
6.063
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
|
| Heavy Atom Count |
29
|
| Complexity |
527
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| Defined Atom Stereocenter Count |
1
|
| SMILES |
O([H])C1C(C2C([H])=C([H])C([H])=C([H])C=2[H])=NC2=C([H])C([H])=C([H])C([H])=C2C=1C(N([H])[C@]([H])(C1C([H])=C([H])C([H])=C([H])C=1[H])C([H])([H])C([H])([H])[H])=O
|
| InChi Key |
BIAVGWDGIJKWRM-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C25H22N2O2/c1-2-20(17-11-5-3-6-12-17)27-25(29)22-19-15-9-10-16-21(19)26-23(24(22)28)18-13-7-4-8-14-18/h3-16,20,28H,2H2,1H3,(H,27,29)/t20-/m0/s1
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| Chemical Name |
3-hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide
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| Synonyms |
SB223412; SB-223412; SB 223412; Talnetant
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: ≥ 100 mg/mL (~261.5 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6147 mL | 13.0736 mL | 26.1472 mL | |
| 5 mM | 0.5229 mL | 2.6147 mL | 5.2294 mL | |
| 10 mM | 0.2615 mL | 1.3074 mL | 2.6147 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00101985 | Completed | Drug: talnetant | Irritable Colon | GlaxoSmithKline | October 2004 | Phase 2 |
| NCT00103727 | Completed | Drug: Talnetant Other: placebo Other: risperidone |
Schizophrenia | GlaxoSmithKline | December 2004 | Phase 2 |
| NCT00300963 | Completed | Drug: Talnetant | Schizophrenia | GlaxoSmithKline | December 2004 | Phase 2 |
| NCT00049946 | Completed | Drug: talnetant Drug: risperidone |
Schizophrenia | GlaxoSmithKline | October 2002 | Phase 2 |
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