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| Targets |
L-838,417 targets GABAA receptors, but with a unique subtype selectivity. It acts as a partial agonist at GABAA receptors containing the α2, α3, and α5 subunits. In contrast, it acts as an antagonist at GABAA receptors containing the α1 subunit. This is a significant feature because the sedative properties of benzodiazepines are primarily mediated by the α1 subunit, while the anxiolytic effects are mediated by the α2 and α3 subunits. By selectively modulating these subtypes, L-838,417 can produce anxiolytic effects with reduced sedation.
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| ln Vitro |
In vitro, L-838,417 potentiates GABA-induced currents in cells expressing α2β3γ2, α3β3γ2, or α5β3γ2 subunit-containing GABAA receptors when used at a concentration of 100 nM. This confirms its activity as a positive modulator at these receptor subtypes. Its lack of effect at the α1 subtype explains its reduced sedative profile. Detailed EC50 values for receptor modulation are not extensively reported in the available literature.
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| ln Vivo |
Adult rats treated with L-838417 (1.0 mg/kg) experience anxiolytic effects, which include a change from social avoidance to preference and an increase in social investigation [2]. Social avoidance is eliminated by L-838417 (2.0 mg/kg), but social inquiry is not anxiolytically affected [2]. All ages had the anxiolytic effects of previous stress reversed by L-838417 (0.5 mg/kg); nevertheless, doses more than 1 mg/kg resulted in a reduction in social investigation, which may be partially explained by the compound's motor-impairing effects [2].
In vivo, L-838,417 produces anxiolytic-like effects in rats. At a dose of 1.0 mg/kg, it transforms social avoidance into preference and increases social investigation in adult rats. It also decreases social avoidance in a novel environment in adult and adolescent rats. Furthermore, L-838,417 (10 mg/kg) increases the mechanical paw withdrawal threshold in a rat model of spinal nerve ligation-induced static allodynia. These in vivo activities confirm its anxiolytic and analgesic potential. |
| Enzyme Assay |
Non-cell-based receptor binding assays for L-838,417 involve radioligand binding studies using membrane preparations from cells expressing specific GABAA receptor subunits. The receptor is incubated with a radiolabeled benzodiazepine ligand and varying concentrations of L-838,417. Binding affinity (Ki) is determined by measuring displacement of the radiolabeled ligand. Selectivity profiling against α1, α2, α3, and α5 subunit-containing receptors is performed to confirm specificity.
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| Cell Assay |
Cellular assays for L-838,417 are performed using cells expressing specific GABAA receptor subunits (α2β3γ2, α3β3γ2, α5β3γ2). Cells are treated with the compound at various concentrations, and receptor activity is measured using electrophysiological techniques (patch-clamp) or fluorescence-based membrane potential assays. The compound's ability to potentiate GABA-induced currents is quantified. These assays confirm its functional activity as a positive modulator.
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| Animal Protocol |
Animal/Disease Models: Male and female adolescent and adult SD (SD (Sprague-Dawley)) rats [2].
Doses: 0, 0.5, 1.0, 2.0 or 4.0 mg/kg. Management: Intellectual Property. Experimental Results: Adolescents required a higher dose (2 mg/kg) to attenuate their social avoidance. The lowest dose of 0.5 mg/kg was sufficient to reverse the anxiogenic effects of repeated restraint, as reflected by a significant increase in coefficients relative to vehicle-treated animals. In vivo animal models for L-838,417 include models of anxiety, such as the social interaction test in rats. The compound is administered via appropriate routes, and anxiety-like behavior is assessed. Models of pain, such as spinal nerve ligation-induced allodynia, are used to assess its analgesic effects. These studies confirm the compound's anxiolytic and analgesic efficacy. |
| ADME/Pharmacokinetics |
L-838,417 has a molecular weight of 399.41 g/mol and a molecular formula of C₁₉H₁₉F₂N₇O. Its CAS number is 286456-42-6. The compound is supplied as a solid with a purity of ≥95%. It is soluble in DMSO and methanol. Storage conditions: -20°C. The compound is supplied for research use only.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for L-838,417 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 | |
| Additional Infomation |
L-838,417 is a GABAA receptor modulator that acts as a partial agonist at α2-, α3-, and α5-containing receptors and an antagonist at α1-containing receptors. It potentiates GABA-induced currents at α2, α3, and α5 subtypes at 100 nM. It produces anxiolytic effects in rats without sedation. It also has analgesic effects in a model of neuropathic pain. Its CAS number is 286456-42-6.
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| Molecular Formula |
C19H19N7OF2
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|---|---|
| Molecular Weight |
399.39726
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| Exact Mass |
399.162
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| CAS # |
286456-42-6
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| Related CAS # |
L-838417-d9;1213669-91-0
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| PubChem CID |
9908880
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| Appearance |
White to off-white solid powder
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| LogP |
3.074
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
565
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
BQDUNOMMYOKHEP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H19F2N7O/c1-19(2,3)13-8-15-24-25-17(12-7-11(20)5-6-14(12)21)28(15)26-18(13)29-9-16-22-10-23-27(16)4/h5-8,10H,9H2,1-4H3
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| Chemical Name |
7-tert-butyl-3-(2,5-difluorophenyl)-6-[(2-methyl-1,2,4-triazol-3-yl)methoxy]-[1,2,4]triazolo[4,3-b]pyridazine
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| Synonyms |
L-838417; L 838417; L838417
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5038 mL | 12.5188 mL | 25.0376 mL | |
| 5 mM | 0.5008 mL | 2.5038 mL | 5.0075 mL | |
| 10 mM | 0.2504 mL | 1.2519 mL | 2.5038 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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