| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| Other Sizes |
| Targets |
Serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) interaction
ZZL-7 targets the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). By disrupting this interaction, it reduces extracellular 5-HT concentration and downregulates 5-HT1A receptor auto-activity in the DRN. This mechanism enhances 5-HT signaling in forebrain circuits, leading to fast-acting antidepressant effects. The compound's ability to cross the blood-brain barrier supports its central nervous system activity. Its novel mechanism distinguishes it from traditional SSRIs. |
|---|---|
| ln Vitro |
The quantity of SERT-nNOS complex is considerably reduced when grown 293T cells transfected with nNOS and SERT are incubated with ZZL-7 (1.0 μM) for two hours[1].
In vitro studies demonstrate that ZZL-7 disrupts the interaction between SERT and nNOS in the DRN. This disruption reduces extracellular 5-HT concentration and downregulates 5-HT1A receptor auto-activity. The compound's ability to enhance 5-HT signaling in forebrain circuits has been demonstrated in cell-based and tissue-based assays. Its fast-acting antidepressant properties make it a valuable research tool for studying the mechanisms of depression and for developing new treatments. Detailed in vitro characterization data are available in the primary literature. |
| ln Vivo |
Two hours after treatment, in vivo electrophysiology in SERT-Cre mice shows a substantial increase in the firing frequency of serotonergic neurons caused by ZZL-7 (10 mg/kg, intraperitoneally). ZZL-7 shortens the duration of immobility in wild-type mice[1]. Two hours after treatment, intragastric injection of ZZL-7 (10, 20, and 40 mg/kg; once) causes dose-dependent antidepressant-like behaviors[1]. Two hours after treatment, chronic unpredictable moderate stress (CMS)-induced depression behaviors are reversed by ZZL-7 (10 mg/kg; intraperitoneal administration)[1].
In vivo studies of ZZL-7 have demonstrated its fast-acting antidepressant effects. As a compound that disrupts SERT-nNOS interaction in the DRN, it enhances 5-HT signaling in forebrain circuits. The compound easily crosses the blood-brain barrier, supporting its central nervous system activity. Specific in vivo efficacy data in animal models of depression are available in the primary literature. The compound shows promise as a fast-acting treatment for major depressive disorder. Further research is ongoing to characterize its full therapeutic potential. |
| Enzyme Assay |
Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD [1].
For SERT-nNOS interaction assays, DRN tissue or cells expressing SERT and nNOS are treated with varying concentrations of ZZL-7. The interaction between SERT and nNOS is assessed by co-immunoprecipitation (Co-IP) or proximity ligation assays (PLA). 5-HT1A receptor auto-activity is measured by assessing receptor-mediated signaling (e.g., G protein activation, cAMP inhibition). Extracellular 5-HT concentration is measured by microdialysis or HPLC. For binding assays, receptor binding affinity can be assessed using radiolabeled ligands. |
| Cell Assay |
For in vitro cellular assays, cells expressing SERT and nNOS (e.g., neuronal cell lines or primary DRN neurons) are cultured in appropriate media under standard conditions (37°C, 5% CO2). ZZL-7 is dissolved in DMSO and diluted in culture medium to desired concentrations. Cells are treated with compound for specified durations. SERT-nNOS interaction is assessed by Co-IP or PLA. 5-HT uptake is measured using radiolabeled [3H]-5-HT. 5-HT1A receptor signaling is assessed by measuring cAMP levels or G protein activation. Cell viability and cytotoxicity can be assessed using standard assays. Each concentration is tested in replicate wells with vehicle controls.
|
| Animal Protocol |
Animal/Disease Models: SERT-Cre mice[1]
Doses: 10 mg/kg Route of Administration: ip; once Experimental Results: Dramatically increased firing frequency of serotonergic neurons 2 hrs (hours) after treatment in vivo electrophysiology in SERT-Cre mice. For in vivo animal studies, ZZL-7 is typically formulated in suitable vehicles and administered via intraperitoneal (i.p.) injection or oral gavage. Dosing regimens vary by study objective. In depression models (e.g., forced swim test, tail suspension test, chronic mild stress), animals are treated with compound and behavioral responses are recorded. Extracellular 5-HT levels in the DRN and forebrain can be measured by microdialysis. SERT-nNOS interaction in the DRN can be assessed ex vivo by Co-IP. All procedures must follow institutional animal care and use committee guidelines. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of ZZL-7 indicate it easily crosses the blood-brain barrier. The compound has a molecular weight of 244.14 and formula C11H20N2O4. CAS number: 99141-91-0. Storage: typically at -20°C for powder; in solvent at -80°C. Solubility: soluble in DMSO and other organic solvents. As a small-molecule antidepressant, it is expected to have favorable oral bioavailability and brain penetration. Specific pharmacokinetic parameters such as half-life, clearance, and bioavailability are reported in the primary literature.
|
| Toxicity/Toxicokinetics |
According to available safety information, ZZL-7 is intended for research purposes only and is not for human therapeutic use. Standard laboratory safety precautions should be followed when handling this compound, including the use of appropriate personal protective equipment (gloves, lab coat, safety goggles). The compound should be handled in a well-ventilated area. Avoid dust formation and inhalation. In case of skin contact, wash with plenty of soap and water. In case of eye contact, rinse cautiously with water for several minutes. No clinical toxicity data are available.
|
| References | |
| Additional Infomation |
ZZL-7 is a fast-acting antidepressant that disrupts SERT-nNOS interaction in the DRN, reduces extracellular 5-HT concentration, and downregulates 5-HT1A receptor auto-activity. It enhances 5-HT signaling in forebrain circuits and easily crosses the blood-brain barrier. It shows promise as a fast-acting treatment for major depressive disorder. It has a molecular weight of 244.14 and formula C11H20N2O4. It is for research use only with no regulatory approvals reported.
|
| Molecular Formula |
C11H20N2O4
|
|---|---|
| Molecular Weight |
244.29
|
| Exact Mass |
244.142
|
| Elemental Analysis |
C, 54.08; H, 8.25; N, 11.47; O, 26.20
|
| CAS # |
99141-91-0
|
| PubChem CID |
166176924
|
| Appearance |
White to off-white oil
|
| LogP |
-0.2
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
17
|
| Complexity |
302
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)OC)NC(=O)C
|
| InChi Key |
RHDUVXUSBMPQOK-CBAPKCEASA-N
|
| InChi Code |
InChI=1S/C11H20N2O4/c1-6(2)9(11(16)17-5)13-10(15)7(3)12-8(4)14/h6-7,9H,1-5H3,(H,12,14)(H,13,15)/t7-,9-/m0/s1
|
| Chemical Name |
methyl (2S)-2-[[(2S)-2-acetamidopropanoyl]amino]-3-methylbutanoate
|
| Synonyms |
ZZL-7; ZZL7; ZZL 7
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: 250 mg/mL (1023.37 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (8.51 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 (8.51 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 (8.51 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 | 4.0935 mL | 20.4675 mL | 40.9350 mL | |
| 5 mM | 0.8187 mL | 4.0935 mL | 8.1870 mL | |
| 10 mM | 0.4093 mL | 2.0467 mL | 4.0935 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
