| Size | Price | Stock | Qty |
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| 1mg |
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| 100mg | |||
| Other Sizes |
| Targets |
5-HT6 receptor (Ki = 1.43 ± 0.0216 nM for 5HT6-ligand-1) [1]
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| ln Vitro |
5HT6-ligand-1 showed potent binding affinity toward human 5-HT6 receptor with a Ki value of 1.43 nM. [1]
In a functional activity assay, 5HT6-ligand-1 exhibited a Kb value of 0.59 ± 0.36 nM, an IC50 of 135.1 ± 19.79 nM, and an Imax of 100 ± 0.14%. [1] Cross‑selectivity profiling at 1 µM concentration revealed the following percent inhibition: α1B 2.26%, 5‑HT2A 23.98%, 5‑HT3 18.82%, D2 11.08%, D3 27.8%, DAT 3.66%, NET 10.83%, SERT 4.62%, H1 9.48%, hERG 15.75% for 5HT6-ligand-1. [1] 5HT6-ligand-1 inhibited CYP3A4 with an IC50 of 35.97 µM and CYP2D6 with an IC50 of 19.50 µM. [1] In human liver microsomes, 5HT6-ligand-1 showed 90% metabolism at 0.5 h (2.5 µM concentration); in rat liver microsomes, 100% metabolism was observed under the same conditions. [1] |
| ln Vivo |
Rat liver microsomes exhibit significant 5HT6-ligand-1 metabolization, while human liver microsomes exhibit 90% extensive 5HT6-ligand-1 metabolization. 5HT6-ligand-1's IC50 value on CYP 3A4 is 35.97%, whereas it is less than 20 μM for CYP 2D6. Rats injected with 10 mg/kg of 5HT6-ligand-1 absorbed it quickly, with an oral bioavailability of 29±5% and a good oral half-life of 3.17±0.49 h. At 1.83 hours, the oral Cmax was recorded as 60±44 ng/mL. Oral exposure of 217±92 ng h/mL was demonstrated by 5HT6-ligand-1. The intravenous administration yields a volume of distribution of 32.6±10.7 L/kg and a clearance rate of 220±92 mL/min/kg. 5HT6-ligand-1 has a moderate oral bioavailability, which could be explained by extensive rat metabolism combined with high clearance. The potential for compound 6a to improve cognitive function was demonstrated by the oral administration of 5HT6-ligand-1, which reversed temporal delay-induced memory deficits. A statistically significant effect was observed at a dose of 10 mg/kg.
Oral administration of 5HT6-ligand-1 at 10 mg/kg significantly reversed time‑delay induced memory deficit in the Object Recognition Task (ORT) in male Wistar rats (statistically significant effect, P < 0.05). [1] In a steady‑state brain penetration study in male Wistar rats, the brain‑to‑plasma concentration ratio (Cb/Cp) of 5HT6-ligand-1 was 20.33. [1] |
| Enzyme Assay |
The in vitro 5‑HT6 receptor binding assay was performed using human recombinant receptor expressed in HEK293 cells. The radioligand used was [³H]‑LSD (specific activity 60‑80 Ci/mmol) at a final concentration of 1.5 nM. Non‑specific binding was determined using methionine myelinate (0.1 µM). Methiothepin mesylate served as the reference compound and positive control. Displacement of [³H]‑LSD binding to cloned human 5‑HT6 receptors was measured, and Ki values were calculated. All synthesized compounds, including 5HT6-ligand-1, were tested for binding affinity. [1]
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| Cell Assay |
Functional activity of 5HT6-ligand-1 was determined using a non‑radioactive cell‑based assay. The assay provided Kb and IC50 values. The Kb value for 5HT6-ligand-1 was 0.59 ± 0.36 nM, the IC50 was 135.1 ± 19.79 nM, and the maximal inhibition (Imax) was 100 ± 0.14%. These values represent the mean of two experiments. [1]
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| Animal Protocol |
For the pharmacokinetic study, fasted male Wistar rats were used. The vehicle was water for injection. Oral dosing volume was 10 mL/kg, and intravenous dosing volume was 2 mL/kg. 5HT6-ligand-1 was administered orally at 10 mg/kg and intravenously (exact iv dose not specified). Blood samples were collected to determine pharmacokinetic parameters. [1]
For the Object Recognition Task (ORT), male Wistar rats (n = 6‑9 per group) were treated orally with 5HT6-ligand-1 or vehicle (PEG 400 50% v/v; 1 mL/kg). Drug or vehicle was administered 60 minutes prior to the test. The test evaluated reversal of time‑delay induced memory deficit. [1] For the steady‑state brain penetration study, male Wistar rats were used, and the brain‑to‑plasma concentration ratio (Cb/Cp) for 5HT6-ligand-1 was determined. [1] |
| ADME/Pharmacokinetics |
After oral administration of 5HT6-ligand-1 at 10 mg/kg in male Wistar rats, the compound was rapidly absorbed with an oral half‑life of 3.17 ± 0.49 h, an oral bioavailability of 29 ± 5%, a peak plasma concentration (Cmax) of 60 ± 44 ng/mL occurring at Tmax of 1.83 h, and an oral exposure (AUC) of 217 ± 92 ng·h/mL. [1]
After intravenous administration (dosing volume 2 mL/kg), 5HT6-ligand-1 showed a clearance (CL) of 220 ± 40 mL/min/kg, a volume of distribution (Vz) of 32.6 ± 10.7 L/kg, and an intravenous half‑life of 1.76 ± 0.76 h. [1] In human liver microsomes, 5HT6-ligand-1 showed 90% metabolism at 0.5 h (2.5 µM); in rat liver microsomes, 100% metabolism was observed. [1] The steady‑state brain‑to‑plasma concentration ratio (Cb/Cp) of 5HT6-ligand-1 in male Wistar rats was 20.33. [1] |
| Toxicity/Toxicokinetics |
5HT6-ligand-1 showed low potential for drug‑drug interaction, with IC50 values of 35.97 µM for CYP3A4 and 19.50 µM for CYP2D6, indicating no CYP liabilities. [1]
At 1 µM concentration, 5HT6-ligand-1 displayed percent inhibition against several off‑target receptors: α1B 2.26%, 5‑HT2A 23.98%, 5‑HT3 18.82%, D2 11.08%, D3 27.8%, DAT 3.66%, NET 10.83%, SERT 4.62%, H1 9.48%, and hERG 15.75%. [1] |
| References |
[1]. Nirogi RVS, et al. Design, synthesis and pharmacological evaluation of 4-(piperazin-1-yl methyl)-N1-arylsulfonyl indole derivatives as 5-HT6 receptor ligands. Bioorg Med Chem Lett 22 (2012) 7431–7435
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| Additional Infomation |
Cognitive impairment is a defining symptom of neurological disorders such as Alzheimer’s disease, dementia, Parkinson’s disease, and schizophrenia. The 5‑HT6 receptor is exclusively expressed in brain regions associated with learning and memory, making it a promising target for treatment. Antagonism of 5‑HT6 receptors leads to increased cAMP production and selective elevation of glutamate and acetylcholine in the frontal cortex. 5HT6-ligand-1 was designed by moving the CH₂‑piperazinyl moiety from the C5 to the C4 position of the indole nucleus (compared to previous Compounds I), maintaining the pharmacophoric requirements for 5‑HT6 binding: a basic amine moiety and two hydrophobic aryl functionalities. Based on its overall profile (potent binding, good PK, no CYP liabilities, and efficacy in cognitive models), 5HT6-ligand-1 was selected for further development. [1]
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| Molecular Formula |
C20H22BRN3O2S
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|---|---|
| Molecular Weight |
448.376582622528
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| Exact Mass |
447.061
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| CAS # |
1038988-11-2
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| PubChem CID |
24965679
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
603
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1CCN(CC1)CC2=C3C=CN(C3=CC=C2)S(=O)(=O)C4=CC=CC=C4Br
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| InChi Key |
AGKMPGSBLMAGAX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H22BrN3O2S/c1-22-11-13-23(14-12-22)15-16-5-4-7-19-17(16)9-10-24(19)27(25,26)20-8-3-2-6-18(20)21/h2-10H,11-15H2,1H3
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| Chemical Name |
1-(2-bromophenyl)sulfonyl-4-[(4-methylpiperazin-1-yl)methyl]indole
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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 | 2.2303 mL | 11.1513 mL | 22.3025 mL | |
| 5 mM | 0.4461 mL | 2.2303 mL | 4.4605 mL | |
| 10 mM | 0.2230 mL | 1.1151 mL | 2.2303 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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