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| Targets |
L-732138 selectively targets the neurokinin-1 (NK-1) receptor, which is a G protein-coupled receptor for the neuropeptide substance P. It acts as a competitive antagonist, meaning it binds to the same site as the natural ligand, substance P, and blocks its effects. L-732138 exhibits remarkable selectivity, being more than 1000-fold more potent at cloned human NK-1 receptors than at human NK-2 and NK-3 receptors. It is also approximately 200-fold more potent at human NK-1 receptors than at rat NK-1 receptors.
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| ln Vitro |
Cytotoxicity is concentration-dependent and is produced in COLO 858, MEL HO, and COLO 679 cells treated with L-732138 (0 -100 µM; initial doubling time). With an IC50 of 44.6 μM in COLO 858 cells, 76.3 μM in MEL HO cells, and 64.2 μM in COLO 679 cells, L-732138 suppresses cell growth. Substance P (SP) mitogen stimulation is blocked by L-732138 [1]. Following L-732,138 treatment, a significant number of apoptotic cells were discovered in the melanoma cell lines COLO 858, MEL HO, and COLO 679. Three melanoma cell lines had an IC50 concentration of 43.6% apoptotic cells in DAPI-stained cultures, and an IC100 concentration of 51.4% apoptotic cells [1].
In vitro, L-732138 potently inhibits the binding of its ligand to the NK-1 receptor. It demonstrates an IC50 of 2.3 nM for inhibiting the binding of ¹²⁵I-substance P to the human NK-1 receptor stably expressed in CHO cells. Beyond its receptor antagonism, L-732138 has been shown to induce apoptosis and counteract substance P-related mitogenesis in human melanoma cell lines. This indicates that the compound can not only block the receptor's function but also trigger cell death in certain cancer contexts, potentially by inhibiting substance P-driven proliferation. |
| ln Vivo |
Vagus nerve-induced plasma extravasation was eliminated and LPS enhancement was markedly decreased in male Dunkin-Hartley guinea pigs treated with L-732138 (10-4-10-2 mol/kg; intravenous injection; 15 min duration). LPS-enhanced vagus nerve-induced plasma extravasation cannot be fully inhibited by L-732138 or SOD administration alone, but it can be blocked by the combination of the two pretreatments [3].
In vivo, L-732138 has been shown to be effective in reducing hyperalgesia. However, detailed in vivo efficacy data are not extensively reported in the available literature. The compound has been used to study neurogenic plasma exudation in guinea-pig airways. Its primary application is as a research tool to elucidate the physiological and pathological roles of the NK-1 receptor in animal models of pain, inflammation, and other conditions. |
| Enzyme Assay |
Non-cell-based in vitro assays for L-732138 typically involve radioligand binding studies to determine its affinity for the NK-1 receptor. In these assays, membrane preparations from cells expressing the human NK-1 receptor are incubated with a radiolabeled high-affinity antagonist, such as ¹²⁵I-substance P, in the presence of varying concentrations of L-732138. The ability of L-732138 to displace the radiolabeled ligand is measured, and the inhibitory constant (IC50) is calculated from competition curves. This method provides a quantitative measure of the compound's binding affinity, with L-732138 demonstrating an IC50 of 2.3 nM.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: COLO 858, MEL HO and COLO 679 Cell Tested Concentrations: 0 µM, 20 µM, 40 µM, 60 µM, 80 µM, 100 µM Incubation Duration: First Doubling Time Experimental Results: Produced Concentration - dependent cytotoxicity. Cellular assays for L-732138 are used to assess its functional antagonism at the NK-1 receptor. These assays often employ cell lines that stably express the human NK-1 receptor and are engineered to report receptor activation, for example, through a calcium-sensitive fluorescent dye. Cells are pre-incubated with L-732138 and then stimulated with an NK-1 receptor agonist like substance P. The compound's ability to inhibit the agonist-induced signal, such as an increase in intracellular calcium, is measured. The concentration required to produce half-maximal inhibition (IC50) is determined, confirming its potent functional antagonism. |
| Animal Protocol |
Animal/Disease Models: Male Dunkin-Hartley guinea pigs (350-500 g) injected with lipopolysaccharide (LPS) [3]
Doses: 10-4 mol/kg, 10-3 mol/kg and 10-2 mol/kg Route of Administration: intravenous (iv) (iv)Injection Injection; 15 min Experimental Results: Eliminates vagus nerve-induced plasma leakage in tracheobronchial tissue and dose-dependently inhibits vagus nerve-induced plasma leakage in LPS-enhanced tracheobronchial tissue. In vivo animal models for L-732138 include those designed to study pain and inflammation. A commonly used model is the substance P-induced behavioral response in mice, where the compound is administered prior to an intrathecal or central injection of a substance P analog. The reduction in pain-related behaviors, such as scratching and biting, is quantified. Another model involves the inhibition of neurogenic inflammation, such as plasma extravasation in the dura mater, which is relevant to migraine research. In these studies, L-732138 is typically administered at various doses, and its efficacy is compared to vehicle controls. |
| ADME/Pharmacokinetics |
L-732138 has a molecular weight of 472.39 g/mol and a molecular formula of C₂₂H₁₈F₆N₂O₃. Its CAS number is 148451-96-1. It is supplied as a solid with a purity of ≥98% (HPLC). The compound is soluble in DMSO (94 mg/mL) and ethanol, but insoluble in water. For in vivo studies, it can be formulated as a homogeneous suspension in CMC-Na at a concentration of ≥5 mg/mL. Storage conditions: room temperature for the powder.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for L-732138 are not extensively reported in the available literature. As a research compound, its safety profile would need to be established through standard preclinical toxicity assessments. The compound is intended for research use only and is not for human consumption. Standard laboratory safety precautions should be followed when handling the compound.
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| References |
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| Additional Infomation |
L-732138 is a potent, selective, and competitive tachykinin NK-1 receptor antagonist (IC50 = 2.3 nM). It was developed by Merck Sharp and Dohme Ltd. It is used as a research tool to study pain modulation, neurogenic inflammation, and the role of substance P in various diseases. It has also shown anti-tumor effects by inducing apoptosis in melanoma cell lines. Its CAS number is 148451-96-1.
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| Molecular Formula |
C22H18F6N2O3
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|---|---|
| Molecular Weight |
472.39
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| Exact Mass |
472.122
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| CAS # |
148451-96-1
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| PubChem CID |
132837
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| Appearance |
White to off-white solid powder
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| Melting Point |
147-148 ℃(lit.)
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| LogP |
5.387
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
677
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)OCC3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F
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| InChi Key |
BYYQYXVAWXAYQC-IBGZPJMESA-N
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| InChi Code |
InChI=1S/C22H18F6N2O3/c1-12(31)30-19(8-14-10-29-18-5-3-2-4-17(14)18)20(32)33-11-13-6-15(21(23,24)25)9-16(7-13)22(26,27)28/h2-7,9-10,19,29H,8,11H2,1H3,(H,30,31)/t19-/m0/s1
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| Chemical Name |
[3,5-bis(trifluoromethyl)phenyl]methyl (2S)-2-acetamido-3-(1H-indol-3-yl)propanoate
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| Synonyms |
L 732138; L732138; 3,5-bis(TFM)Bz NAcTrp
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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)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~529.23 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6.25 mg/mL (13.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 62.5 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. Solubility in Formulation 2: ≥ 6.25 mg/mL (13.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 62.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1169 mL | 10.5845 mL | 21.1689 mL | |
| 5 mM | 0.4234 mL | 2.1169 mL | 4.2338 mL | |
| 10 mM | 0.2117 mL | 1.0584 mL | 2.1169 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.
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