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| Targets |
The primary molecular target of NMDAR antagonist 3 is the NMDA receptor, a subtype of ionotropic glutamate receptor (iGluR). NMDA receptors are heterotetrameric complexes typically composed of two NR1 subunits and two NR2 subunits (where NR2 subunits can be A, B, C, or D), forming ligand-gated cation channels permeable to Ca2+ and Na+. NMDAR antagonist 3 selectively targets the NR1A/2B subtype of the NMDA receptor, showing some inhibitory activity. As the piperidine metabolite of haloperidol (CPHP), the compound has also been studied for its potential neurotoxic effects, which may involve interactions with other central nervous system targets.
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| ln Vitro |
In vitro, NMDAR antagonist 3 has been evaluated for its ability to inhibit NMDA receptor activity. The compound shows a certain but weak inhibitory activity against the NR1A/2B subtype of the NMDA receptor. While the exact IC₅0 value is not published in the available literature, the compound is documented as having some inhibitory activity. For comparison, reference NMDA antagonists such as ifenprodil (NR2B-selective antagonist) has an IC₅0 of approximately 0.3-1 microM for NR1A/NR2B receptors. As a metabolite of haloperidol, CPHP has also been studied for its cellular toxicity, and it is considered to exhibit brain toxicity, which may contribute to the adverse neurological effects of haloperidol treatment.
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| ln Vivo |
In vivo studies have primarily focused on the role of 4-(4-chlorophenyl)-4-hydroxypiperidine as a metabolite of haloperidol. In rats, after systemic administration of haloperidol, the CPHP metabolite is formed via N-dealkylation in the liver. CPHP concentrations in plasma and tissue homogenates from rats have been analyzed by HPLC with fluorescence detection after pre-column derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). CPHP is considered a potential neurotoxic metabolite, as it may contribute to the adverse extrapyramidal symptoms and tardive dyskinesia associated with chronic haloperidol treatment. However, the parent compound NMDAR antagonist 3 has not been evaluated as a therapeutic agent in animal models.
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| Enzyme Assay |
Non-cellular (cell-free) assays for NMDAR antagonist 3 typically involve radioligand binding to evaluate its affinity for NMDA receptor subtypes. A standard protocol uses membrane preparations from HEK293 cells transfected with human NR1A/NR2B NMDA receptor subunits. Membranes are incubated with [3H]Ifenprodil (a selective NR2B antagonist) at a concentration of 2-4 nM in the presence of varying concentrations of NMDAR antagonist 3 (0.1 nM to 100 microM) in assay buffer (50 mM Tris-HCl, pH 7.4) at 25degC for 60-120 minutes. Non-specific binding is determined in the presence of 10 microM unlabeled ifenprodil. After incubation, bound and free radioligands are separated by rapid vacuum filtration onto glass fiber filters, and radioactivity is measured by liquid scintillation counting. Inhibition curves (percent specific binding vs. log[compound]) are generated, and IC₅0 values are calculated.
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| Cell Assay |
Cell-based experiments for NMDA receptor antagonists typically involve functional calcium flux assays using primary rat cortical neurons or HEK293 cells stably expressing recombinant NR1A/NR2B receptors. Cells are loaded with a calcium-sensitive fluorescent dye (e.g., Fluo-4-AM, 2 microM) in HBSS buffer containing 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid (to prevent dye leakage). Following a 30-minute loading period at 37degC, cells are washed and incubated with varying concentrations of test compound (0.01-100 microM) for 10 minutes prior to stimulation with a mixture containing 100 microM NMDA, 10 microM glycine, and 3 microM glutamate (co-agonists). Fluorescence intensity is measured in real-time using a fluorescence plate reader (excitation 485 nm, emission 520 nm). Antagonist activity is quantified as the percent inhibition of the peak calcium signal relative to control wells.
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| Animal Protocol |
In vivo animal experiments for NMDAR antagonists are conducted in rodent models to evaluate pharmacological effects on learning and memory or for neuroprotective activity. A typical protocol for evaluating novel NMDA antagonists in rats involves intraperitoneal (IP) or oral administration of the test compound at doses ranging from 1 to 30 mg/kg, 30-60 minutes prior to behavioral testing. The forced swim test (FST) or tail suspension test (TST) can be used to assess antidepressant-like effects (as ketamine, an NMDA antagonist, shows rapid antidepressant effects). Alternatively, the Morris water maze or novel object recognition (NOR) test can be used to assess effects on learning and memory. However, for the specific compound NMDAR antagonist 3, detailed in vivo animal data are not available in the published literature.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for NMDAR antagonist 3 are limited, as the compound is not a therapeutic agent. As a metabolite of haloperidol (CPHP), its formation and elimination have been studied in rat models. Following intravenous or oral administration of haloperidol, CPHP is formed via N-dealkylation, likely mediated by cytochrome P450 enzymes (primarily CYP3A4 in humans and CYP2D subfamily in rats). The parent compound is a solid at room temperature with a melting point of 137-140degC and a predicted boiling point of 344.5 +/- 42.0degC. It exhibits good solubility in DMSO (50 mg/mL, 236.19 mM). For in vivo formulation, it can be dissolved in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline or 10% DMSO + 90% corn oil to achieve a clear solution at ≥5 mg/mL (≥23.62 mM) for intraperitoneal or intravenous administration.
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| Toxicity/Toxicokinetics |
The toxicity profile of NMDAR antagonist 3 is not well characterized, but the related compound 4-(4-chlorophenyl)-4-hydroxypiperidine is considered to exhibit brain toxicity as a metabolite of haloperidol. The compound is an organic solid and, as with all research chemicals, may cause skin and eye irritation and may be harmful if swallowed, inhaled, or absorbed through the skin. Standard laboratory safety precautions include handling in a well-ventilated area (chemical fume hood) and wearing appropriate PPE (lab coat, safety glasses, and gloves). The compound should be stored at room temperature and protected from light, as it may be light-sensitive. Detailed acute oral toxicity data (LD₅0) are not available from the current literature.
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| References | |
| Additional Infomation |
Additional information: NMDAR antagonist 3 (Compound 2) is available from commercial suppliers for research and analytical applications. It is intended for research use only and is not approved for human or veterinary use. The compound has a CAS number of 39512-49-7, an InChIKey of YZRKAZMWNAUUPG-UHFFFAOYSA-N, and a molecular formula of C11H14ClNO. Synonyms include 4-(4-Chlorophenyl)piperidin-4-ol; 4-(p-Chlorophenyl)-4-hydroxypiperidine; and p-Chloro-4-hydroxypiperidine. The compound is a member of the piperidine family and is characterized by a piperidine ring with a phenyl group bearing a chlorine atom and a hydroxyl group. This compound has found application as a useful tool for exploring the impact of piperidine-based compounds on the nervous system and as a chemical intermediate for synthesizing more complex pharmacologically active agents targeting CNS receptors.
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| Molecular Formula |
C11H14CLNO
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| Molecular Weight |
211.69
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| Exact Mass |
211.076
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| CAS # |
39512-49-7
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| Related CAS # |
63638-93-7 (hydrochloride)
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| PubChem CID |
38282
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| Appearance |
Typically exists as solids at room temperature
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| Hydrogen Bond Donor Count |
2
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
14
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| Complexity |
184
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CNCCC1(C2=CC=C(C=C2)Cl)O
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| InChi Key |
LZAYOZUFUAMFLD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H14ClNO/c12-10-3-1-9(2-4-10)11(14)5-7-13-8-6-11/h1-4,13-14H,5-8H2
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| Chemical Name |
4-(4-chlorophenyl)piperidin-4-ol
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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 | 4.7239 mL | 23.6194 mL | 47.2389 mL | |
| 5 mM | 0.9448 mL | 4.7239 mL | 9.4478 mL | |
| 10 mM | 0.4724 mL | 2.3619 mL | 4.7239 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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