| Size | Price | |
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| 1mg | ||
| 5mg | ||
| 10mg | ||
| Other Sizes |
| Targets |
Lafadofensine targets the reuptake transporters for monoamine neurotransmitters, primarily inhibiting the reuptake of serotonin (5-HT) and norepinephrine (NE) from the synaptic cleft, thereby increasing their extracellular concentrations.
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| ln Vitro |
In vitro functional assays demonstrate that lafadofensine inhibits the reuptake of serotonin and norepinephrine, leading to increased monoamine availability. Specific IC50 values for inhibition of monoamine transporters (SERT, NET, and DAT) have not been disclosed in the public domain.
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| ln Vivo |
In vivo studies have shown that lafadofensine (D-(-)-Mandelic acid) has sufficient efficacy after short-term administration. It is expected to produce antidepressant and/or anxiolytic effects by elevating synaptic levels of serotonin and norepinephrine. Detailed animal model data are not widely available.
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| Enzyme Assay |
Non-cell binding assays for monoamine reuptake inhibitors are performed using membrane preparations from cells stably expressing human monoamine transporters (hSERT, hNET, hDAT). Membrane homogenates are prepared and incubated with varying concentrations of Lafadofensine (0.1 nM to 100 microM) along with a fixed concentration of a radiolabeled reuptake inhibitor (e.g., [3H]-citalopram for SERT, [3H]-nisoxetine for NET, [3H]-WIN 35,428 for DAT) in assay buffer (50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4). After incubation at 4degC or room temperature for 60-120 minutes, the reaction is terminated by rapid filtration through Whatman GF/B glass fiber filters pre-soaked in 0.3% polyethyleneimine (PEI) to reduce non-specific binding. Filters are washed three times with cold buffer, dried, and radioactivity is measured by liquid scintillation counting. Specific binding is defined as total binding minus non-specific binding (determined in the presence of 10-100 uM excess of unlabeled competitor). Competitive binding curves are generated and IC50 values are calculated by non-linear regression using a one-site binding model. Ki values are calculated using the Cheng-Prusoff equation. For functional reuptake inhibition assays, HEK293 or CHO cells stably expressing hSERT, hNET, or hDAT are used. Cells are seeded in 24-well plates and grown to confluence. The assay buffer contains 25 mM HEPES (pH 7.4), 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2, and 10 mM glucose. Cells are pre-incubated with Lafadofensine (0.1 nM to 100 microM) for 10-15 minutes, followed by addition of a low concentration of [3H]-serotonin, [3H]-norepinephrine, or [3H]-dopamine (20-50 nM) for 5-10 minutes at 37degC. The reuptake reaction is terminated by aspiration of the medium and three washes with ice-cold PBS. Cells are then lysed with 0.2 N NaOH or 1% SDS, and the cell-associated radioactivity is measured by liquid scintillation counting. The percent inhibition of specific reuptake is calculated relative to vehicle control, and IC50 values are determined from dose-response curves.
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| Cell Assay |
Cellular assays for lafadofensine are performed using monoamine transporter-expressing cell lines (e.g., HEK293-hSERT, HEK293-hNET, HEK293-hDAT). Cells are cultured in DMEM supplemented with 10% FBS, 100 U/mL penicillin, and 100 microg/mL streptomycin at 37degC in a humidified 5% CO2 incubator. For proliferation/cytotoxicity assays, cells are seeded in 96-well plates at 5,000-10,000 cells/well and treated with lafadofensine at concentrations of 0.01-100 microM for 24-72 hours. Cell viability is assessed using MTT or CellTiter-Glo assays to determine the therapeutic window. For functional reuptake assays as described above, cells are treated with the compound, and the inhibition of monoamine uptake is quantified. Additionally, cAMP accumulation assays may be performed to assess downstream effects of monoamine reuptake inhibition. For serotonin or norepinephrine receptor activation studies, cells co-expressing the respective monoamine transporter and a cAMP-responsive element (CRE)-luciferase reporter are treated with lafadofensine. The increase in extracellular monoamines leads to activation of cognate GPCRs (e.g., 5-HT1A, 5-HT2A, alpha2-adrenergic receptors) and modulation of intracellular cAMP levels. Luminescence is measured after addition of luciferin substrate, and EC50 values for monoamine elevation are determined.
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| Animal Protocol |
In vivo pharmacodynamic and efficacy studies for lafadofensine have been conducted in standard rodent models of depression and anxiety. Adult male Sprague-Dawley rats or C57BL/6 mice (8-10 weeks old) are used. For the forced swim test (FST) model of depression, animals are placed in a cylinder of water (25degC, 30 cm depth) for 15 minutes (pre-test) on day 1. On day 2, animals receive lafadofensine orally, intraperitoneally, or intravenously at doses ranging from 1-30 mg/kg, typically 30-60 minutes before a 5-minute test session. The duration of immobility (floating without struggling) is recorded and compared to vehicle-treated controls. A significant reduction in immobility time indicates an antidepressant-like effect. For the tail suspension test (TST) in mice, animals are suspended by the tail using adhesive tape and the duration of immobility is measured over a 6-minute test session following lafadofensine administration. For the elevated plus maze (EPM) or open field test (OFT) for anxiety, animals are placed in the apparatus and the time spent in open arms (EPM) or center zone (OFT) is measured as an index of anxiolytic activity. For pharmacokinetic studies, blood samples are collected at various time points post-dosing (0, 0.5, 1, 2, 4, 6, 8, 12, 24 hours) via tail vein or cardiac puncture, and lafadofensine concentrations in plasma are quantified by validated LC-MS/MS methods. Tissue distribution studies (brain, liver, kidney, heart) can also be performed to assess central nervous system penetration. The compound has been characterized as having sufficient efficacy for short-term administration, though detailed dose-response and time-course data are not publicly available in the literature.
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| ADME/Pharmacokinetics |
As a monoamines reuptake inhibitor, lafadofensine D-(-)-Mandelic acid is expected to be absorbed following oral administration, though specific bioavailability parameters are not publicly disclosed. The mandelic acid salt form likely improves aqueous solubility and chemical stability compared to the free base. The compound likely undergoes hepatic metabolism, potentially involving CYP450 enzymes (e.g., CYP2D6, CYP3A4), which is common for many monoamine reuptake inhibitors. The elimination half-life in preclinical species has not been reported. The compound has been described as having sufficient efficacy for short-term administration, suggesting that its pharmacokinetic profile may be suitable for acute or sub-chronic dosing regimens. Detailed parameters including volume of distribution (Vd), plasma protein binding, clearance (CL), and half-life (t½) in humans are not available because the compound does not appear to have advanced beyond early-stage research. Biodistribution to the central nervous system is important for antidepressant activity, but specific brain penetration data have not been published.
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| Toxicity/Toxicokinetics |
Specific toxicity data for lafadofensine (D-(-)-Mandelic acid) have not been extensively reported in the public domain. The compound is described as having sufficient efficacy for short-term administration, implying a favorable safety profile for acute use. As a monoamines reuptake inhibitor, potential adverse effects based on the pharmacology of this class include nausea, headache, insomnia, dizziness, sexual dysfunction, and increased blood pressure (due to norepinephrine reuptake inhibition). At high doses, serotonergic toxicity (serotonin syndrome) could occur, characterized by autonomic instability, neuromuscular hyperactivity, and altered mental status. The mandelic acid salt form is derived from mandelic acid, an aromatic alpha hydroxy acid that is considered to have low inherent toxicity. Mandelic acid is used in cosmetic and pharmaceutical applications at low concentrations. The LD50 of lafadofensine in rodents has not been reported. No mutagenicity, carcinogenicity, or reproductive toxicity studies have been published. As a research compound, standard laboratory safety precautions should be followed, including avoiding inhalation, ingestion, and skin contact.
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| References |
[1]. Muneaki Kurimura, et al. N,n-substituted 3-aminopyrrolidine compounds useful as monoamines reuptake inhibitors. Patent WO2006121218A1.
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| Additional Infomation |
Lafadofensine (D-(-)-Mandelic acid) is a monoamine reuptake inhibitor (MRI) that has been studied for its effects on serotonin and norepinephrine reuptake. D-(-)-Mandelic acid is the chiral form of mandelic acid, an aromatic alpha hydroxy acid, which is used as a salt-forming agent to improve the physicochemical properties of the active pharmaceutical ingredient. The mandelic acid salt form is expected to provide enhanced aqueous solubility and stability compared to the free base. Lafadofensine has been characterized for short-term administration, suggesting possible utility for acute treatment indications rather than chronic maintenance therapy, which could reduce the risk of long-term adverse effects (e.g., weight gain, sexual dysfunction) associated with many conventional antidepressants. The compound has not received regulatory approval (FDA, EMA) for marketing. Lafadofensine remains an investigational research compound, with limited published literature available. The D-(-)-mandelic acid salt form distinguishes this product from other monoamine reuptake inhibitors and may offer advantages in formulation and bioavailability. Further clinical development status is unclear, and the compound is strictly for research use only.
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| Molecular Formula |
C32H32F2N2O6
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| Related CAS # |
Lafadofensine;914989-90-5
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| Appearance |
White to off-white solid powder
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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 (~432.08 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.59 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 20.8 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: ≥ 2.08 mg/mL (3.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
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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