| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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Purity: ≥98%
| Targets |
L-655708's primary target is the benzodiazepine site of GABAA receptors that contain the α5 subunit. It acts as an inverse agonist at this site, meaning it binds to the benzodiazepine site and produces an effect opposite to that of benzodiazepine agonists. It has a Ki of 0.45 nM for α5 subunit-containing GABAA receptors, indicating extremely high affinity. This high selectivity for the α5 subunit makes L-655708 a valuable tool for studying the specific role of α5-GABAA receptors in cognitive function, as these receptors are predominantly expressed in the hippocampus and are involved in learning and memory processes.
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| ln Vitro |
L655708, with a Ki of 0.45 nM, is a strong and specific inverse agonist of the GABAA receptor's α5 subunit-containing benzodiazepine site. Compared to GABAA receptors with α1, α2, α3, or α6 subunits and a combination of β3 and γ2, selectivity is 50–100 times better. enhances spatial learning and improves LTP in a slice model of the rat hippocampus without exhibiting proconvulsant activity.
In vitro, L-655708 is a potent and selective inverse agonist for the benzodiazepine site of GABAA receptors containing the α5 subunit. It exhibits a Ki of 0.45 nM for α5-containing GABAA receptors. The compound's high affinity and selectivity for the α5 subunit allow researchers to specifically modulate the activity of this GABAA receptor subtype without significantly affecting other GABAA receptor subtypes that contain different α subunits. This selectivity is crucial for dissecting the distinct roles of different GABAA receptor subtypes in brain function. |
| ln Vivo |
L-655708, administered intraperitoneally at 0.7 mg/kg, it causes modest binding to GABAA receptors containing α1, α2, and α3 subunits, 60–70% occupancy of α5 GABAA receptors, and no discernible behavioral off-target effects. Dizziness and mobility impairments are two examples.
In vivo, L-655708 has been studied for its effects on cognitive function, particularly learning and memory. As an inverse agonist at α5-containing GABAA receptors, it reduces the inhibitory effects of GABA at these receptors, which can enhance cognitive performance. Studies have shown that inverse agonists at α5-GABAA receptors can improve learning and memory in animal models. The compound's ability to selectively target α5-GABAA receptors makes it a valuable tool for studying the role of these receptors in cognitive processes and for exploring potential therapeutic applications in cognitive disorders. |
| Enzyme Assay |
The in vitro activity of L-655708 is assessed using radioligand binding assays and electrophysiological techniques. In radioligand binding assays, membrane preparations from cells or tissues expressing GABAA receptors containing the α5 subunit are incubated with a radiolabeled benzodiazepine site ligand (e.g., [3H]flumazenil or [3H]Ro15-1788) in the presence of varying concentrations of L-655708. The displacement of the radiolabeled ligand is measured to determine the inhibition constant (Ki). The selectivity of L-655708 for α5-containing GABAA receptors over other GABAA receptor subtypes (e.g., α1, α2, α3-containing) is assessed by performing the binding assay with each subtype separately. In functional assays, the inverse agonist activity of L-655708 is assessed using electrophysiological techniques such as patch-clamp recording on cells expressing α5-containing GABAA receptors. The compound's ability to reduce GABA-evoked currents is measured.
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| Cell Assay |
For cellular assays, cell lines expressing GABAA receptors containing the α5 subunit (e.g., HEK293 cells stably or transiently transfected with α5, β3, and γ2 subunits) are used. Cells are cultured in appropriate media (e.g., DMEM with 10% fetal bovine serum) and treated with various concentrations of L-655708 (typically ranging from 0.01 nM to 10 µM) in the presence of a sub-maximal concentration of GABA. The functional activity of L-655708 as an inverse agonist is assessed by measuring its effect on GABA-evoked currents using patch-clamp electrophysiology or by measuring changes in intracellular chloride levels using fluorescent dyes. The compound's ability to reduce the inhibitory effect of GABA at α5-GABAA receptors is quantified.
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| Animal Protocol |
In vivo, L-655708 is typically administered to animal models via intraperitoneal or intracerebroventricular injection. The compound is formulated in a suitable vehicle (e.g., saline or a mixture of DMSO and saline) and administered at various doses (e.g., 0.1-10 mg/kg). Its effects on cognitive function are assessed in behavioral tests such as the Morris water maze, the radial arm maze, or the novel object recognition test. The compound's effects on hippocampal-dependent learning and memory are of particular interest due to the high expression of α5-GABAA receptors in the hippocampus.
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| ADME/Pharmacokinetics |
L-655708 has a molecular weight of 341.36 g/mol and a molecular formula of C18H19N3O4. Its CAS number is 130477-52-0. The compound is typically provided as a solid powder with high purity (≥98%). It is soluble in DMSO and other organic solvents. For in vivo administration, it can be formulated in appropriate vehicles.
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| Toxicity/Toxicokinetics |
Specific toxicity data for L-655708 is not detailed in the provided search results. As an inverse agonist at α5-containing GABAA receptors, its side effect profile would be related to reduced GABAergic inhibition at these receptors. Potential effects may include anxiety, increased arousal, and pro-convulsant activity, which are opposite to the effects of benzodiazepine agonists. However, the high selectivity for the α5 subunit may limit some of these effects. Comprehensive toxicological studies are required to establish its full safety profile.
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| References | |
| Additional Infomation |
L-655708 is a research compound that was developed as a potent and selective inverse agonist for the benzodiazepine site of GABAA receptors containing the α5 subunit. It was first synthesized by Merck, Sharp and Dohme in 1996. The compound's high affinity (Ki = 0.45 nM) and selectivity for the α5 subunit make it a valuable tool for studying the role of α5-GABAA receptors in cognitive function, particularly learning and memory. It is used in research to investigate the potential of α5-GABAA receptor inverse agonists as cognitive enhancers for the treatment of memory disorders. L-655708 is not approved for clinical use and is intended for research purposes only.
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| Molecular Formula |
C18H19N3O4
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| Molecular Weight |
327.33458
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| Exact Mass |
341.138
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| CAS # |
130477-52-0
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| PubChem CID |
5311203
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| Appearance |
White to yellow solid powder
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| Density |
1.42g/cm3
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| Boiling Point |
584.4ºC at 760mmHg
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| Flash Point |
307.2ºC
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| Vapour Pressure |
1.21E-13mmHg at 25°C
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| Index of Refraction |
1.675
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| LogP |
2.286
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
25
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| Complexity |
542
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCOC(=O)C1=C2[C@@H]3CCCN3C(=O)C4=C(N2C=N1)C=CC(=C4)OC
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| InChi Key |
YKYOQIXTECBVBB-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C18H19N3O4/c1-3-25-18(23)15-16-14-5-4-8-20(14)17(22)12-9-11(24-2)6-7-13(12)21(16)10-19-15/h6-7,9-10,14H,3-5,8H2,1-2H3/t14-/m0/s1
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| Chemical Name |
ethyl (13aS)-7-methoxy-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate
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| Synonyms |
L-655708 L655708 FG-8094L 655708 FG 8094L-655,708 L655,708 L 655,708 FG8094.
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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 : ~10 mg/mL (~29.29 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (2.93 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 1 mg/mL (2.93 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 10.0 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: ≥ 1 mg/mL (2.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0550 mL | 15.2751 mL | 30.5502 mL | |
| 5 mM | 0.6110 mL | 3.0550 mL | 6.1100 mL | |
| 10 mM | 0.3055 mL | 1.5275 mL | 3.0550 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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