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| Targets |
Rat 5-HT7 Receptor 8.19 (pKi, in HEK293 cells ) Human 5-HT7 Receptor 8.20 (pKi, in HEK293 cells )
JNJ-18038683 targets the serotonin 5-HT7 receptor. It is a potent and selective antagonist with pKi values of 8.19 and 8.20 for rat and human 5-HT7 receptors, respectively. It decreases 5-HT-stimulated adenylyl cyclase with pKb values of 8.01 (rat) and 7.99 (human). By blocking 5-HT7 receptors, the compound modulates serotonergic signaling pathways involved in mood regulation, circadian rhythm, and thermoregulation. |
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| ln Vitro |
High affinity [3H]5-CT binding sites from the rat and human 5-HT7 receptors expressed in HEK293 cells were displaced by JNJ-18038683 (pKi=8.19±0.02 and 8.20±0.01, respectively). On the natural 5-HT7 in rat thalamus membranes, comparable values (pKi=8.50±0.20) are found. The values of the hill slope are nearly equal to one, indicating one-site competitive binding. The assessment of adenylate cyclase activity in HEK293 cells expressing the human or rat 5-HT7 receptor determines the antagonist potency of JNJ-18038683. Rat and human 5-HT7/HEK293 cells exhibit enhanced adenylyl cyclase activity in response to 5-HT, with pEC50 values of 8.09 and 8.12, respectively. The concentration-dependent reduction of 5-HT (100 nM)-stimulated adenylyl cyclase is seen while using JNJ-18038683. The related Ki values from [3H]5-CT binding studies[1] and the pKB values found for JNJ-18038683 accord well.
In vitro, JNJ-18038683 acts as a potent and selective 5-HT7 receptor antagonist. Its activity is typically assessed by measuring its ability to inhibit 5-HT-stimulated cAMP accumulation in cells expressing 5-HT7 receptors. The compound shows pKi values of 8.19 and 8.20 for rat and human 5-HT7 receptors, respectively. It decreases 5-HT (100 nM)-stimulated adenylyl cyclase in rat and human 5-HT7/HEK293 cells with pKb values of 8.01 and 7.99, respectively. Standard in vitro assays include receptor binding studies using radiolabeled ligands and functional assays measuring cAMP accumulation. |
| ln Vivo |
REM sleep is dose-dependently suppressed by JNJ-18038683, often in the first four hours following therapy. After oral delivery, the duration of REM sleep is considerably reduced during the first four hours (P<0.05) starting at a dose of 1 mg/kg. Alongside this, there is a tendency for the REM sleep latency to be prolonged in a dosage-related manner. Only at the highest tested dose (10 mg/kg; P<0.05) does there appear to be a significant increase in REM latency. These changes in REM sleep appear to be condition-specific. A further investigation is carried out to ascertain whether the repeated administration of JNJ-18038683 for a duration of seven days would lead to any modification of the EEG sleep response, specifically on REM sleep, in rats both during and following treatment. For seven days in a row, JNJ-18038683 is given subcutaneously at a dose of 1 mg/kg every day, two hours into the light phase. JNJ-18038683 causes a prolonging of the REM sleep latency and a considerable reduction in the amount of time spent in REM sleep within the first eight hours following the injection on the first day of treatment. During the seven days of repeated treatment, the REM sleep latency increases; on the first recovery day following treatment termination, it returns to normal. Throughout the seven-day repeated treatment, there is no discernible increase in the amount of time spent in REM sleep; instead, a rebound takes place on the first recovery day following treatment termination. Throughout the course of the treatment, neither the NREM sleep latency nor the total NREM sleep duration are impacted[1].
In vivo, JNJ-18038683 has been shown to be effective in models of depression. As a 5-HT7 receptor antagonist, it would be expected to modulate serotonergic signaling and affect mood regulation. The compound has also been shown to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. However, comprehensive in vivo efficacy data from published literature are limited. The compound is primarily used as a research tool to study 5-HT7 receptor function. |
| Enzyme Assay |
For non-cell-based receptor binding assays, JNJ-18038683 can be evaluated using membrane preparations from cells expressing rat or human 5-HT7 receptors. Radioligand binding displacement experiments are performed using a suitable radiolabeled ligand such as [3H]-5-CT or [3H]-LSD. Membrane homogenates are incubated with increasing concentrations of the test compound and a fixed concentration of the radioligand at room temperature for 60-90 minutes. Bound radioligand is separated from free by rapid filtration through glass fiber filters. Non-specific binding is determined in the presence of excess unlabeled 5-HT. pKi values are calculated from displacement curves using nonlinear regression analysis.
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| Cell Assay |
For in vitro cellular assays, cells expressing rat or human 5-HT7 receptors (e.g., HEK293 cells) are cultured in appropriate media. For functional assays, cAMP accumulation is measured as 5-HT7 receptors are Gs-coupled. Cells are treated with various concentrations of JNJ-18038683 in the presence of 5-HT (100 nM) to stimulate adenylyl cyclase. cAMP levels are measured using ELISA or HTRF-based detection. The compound's ability to inhibit 5-HT-stimulated cAMP accumulation is assessed, and pKb values are calculated from dose-response curves.
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| Animal Protocol |
For in vivo animal studies, JNJ-18038683 can be administered to rodents via intraperitoneal injection. In models of depression (e.g., forced swim test, tail suspension test, or chronic mild stress model), behavioral responses are assessed following compound administration. In models of sleep, REM latency and duration are measured. Dosing regimens vary depending on the specific model and desired exposure levels. Blood and tissue samples may be collected for pharmacokinetic analysis.
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| ADME/Pharmacokinetics |
JNJ-18038683 has a molecular weight of 348.44 and a molecular formula of C21H24N4O. It is a potent and selective 5-HT7 receptor antagonist. The compound is supplied as a research-grade compound. It should be stored at -20°C for long-term stability. It is soluble in DMSO and can be formulated for both in vitro and in vivo administration. It is for research use only and is not intended for human consumption.
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| Toxicity/Toxicokinetics |
The toxicity profile of JNJ-18038683 has not been extensively reported. As a 5-HT7 receptor antagonist, potential adverse effects may include modulation of serotonergic signaling, which could affect mood, sleep, and thermoregulation. The compound is for research use only and is not intended for human consumption. Standard toxicological evaluation would include acute and repeated-dose toxicity studies.
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| References | |
| Additional Infomation |
JNJ-18038683 (CAS 851376-05-1) is a potent and selective antagonist of the 5-HT7 receptor. It exhibits pKi values of 8.19 and 8.20 for rat and human 5-HT7 receptors in cell-based assays, respectively. It decreases 5-HT-stimulated adenylyl cyclase with pKb values of 8.01 (rat) and 7.99 (human). It has been shown to be effective in models of depression. It is available for research purposes only.
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| Molecular Formula |
C26H28CLN3O7
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| Molecular Weight |
529.96942615509
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| Exact Mass |
529.161
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| CAS # |
851376-05-1
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| PubChem CID |
11249539
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
37
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| Complexity |
618
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(CC(CC(O)=O)(C(O)=O)O)O.ClC1C=CC(C2C3CCNCCC=3N(CC3C=CC=CC=3)N=2)=CC=1
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| InChi Key |
DIQZMBPDLFAJLK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H20ClN3.C6H8O7/c21-17-8-6-16(7-9-17)20-18-10-12-22-13-11-19(18)24(23-20)14-15-4-2-1-3-5-15;7-3(8)1-6(13,5(11)12)2-4(9)10/h1-9,22H,10-14H2;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)
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| Chemical Name |
1-benzyl-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[3,4-d]azepine;2-hydroxypropane-1,2,3-tricarboxylic acid
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: 200 mg/mL (377.38 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (9.43 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 50.0 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: ≥ 5 mg/mL (9.43 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 50.0 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: ≥ 5 mg/mL (9.43 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 | 1.8869 mL | 9.4345 mL | 18.8690 mL | |
| 5 mM | 0.3774 mL | 1.8869 mL | 3.7738 mL | |
| 10 mM | 0.1887 mL | 0.9434 mL | 1.8869 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.
Link: https://clinicaltrials.gov/ct2/show/NCT02466685
Conditions:Bipolar DisorderLink: https://clinicaltrials.gov/ct2/show/NCT03633357
Conditions:Bipolar DisorderLink: https://clinicaltrials.gov/ct2/show/NCT00566202
Conditions:Major Depressive DisorderProducts are for research use only; We do not sell to patients
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