| Size | Price | Stock | Qty |
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| Targets |
The primary target of Zanapezil is acetylcholinesterase (AChE), the enzyme responsible for hydrolyzing acetylcholine (ACh) in the synaptic cleft. It is a potent, reversible, and selective inhibitor of AChE. It also shows moderate inhibition of muscarinic M1 and M2 receptor binding (Ki=234 nM and 340 nM, respectively), but its primary mechanism is AChE inhibition.
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| ln Vitro |
In homogenates of the rat cerebral cortex, zanapezil (TAK-147) free base exhibits a strong and reversible suppression of AChE activity (IC50=51.2 nM). Its potency is 3.0- and 2.4-fold greater than that of tacrine and physostigmine, respectively. The least effective inhibitor of butyrylcholinesterase activity in rat plasma is zanapezil free base (IC50=23,500 nM)[1]. Noradrenaline and serotonin absorption is considerably inhibited by zanapezil free base, with IC50 values of 4020 and 1350 nM, respectively[1]. With Ki values of 324, 2330, and 3510 nM, respectively, zanapezil free base also inhibits ligand binding to alpha-1, alpha-2, and serotonin 2 receptors[1].
In vitro, Zanapezil potently and reversibly inhibits AChE activity in homogenates of the rat cerebral cortex with an IC50 of 51.2 nM. It shows moderate inhibition of muscarinic M1 and M2 receptor binding with Ki values of 234 nM and 340 nM, respectively. This combination of strong AChE inhibition and weak muscarinic binding distinguishes it from some other AChE inhibitors. |
| ln Vivo |
In the rat brain, oral treatment of Zanapezil (TAK-147; 3 mg/kg) free base markedly increased the rates of dopamine, noradrenaline, and serotonin turnover. In ex vivo investigations, oral injection of 1–10 mg/kg of Zanapezil free base causes a statistically significant and dose-dependent decrease in AChE activity in the cerebral cortex[1]. For 120 minutes, the ventral hippocampus (VH) considerably raises its ACh level when zanapezil (TAK-147; 5 and 10 mg/kg) is given free base[2].
In vivo, oral administration of Zanapezil (2 mg/kg p.o. for 21 days) in freely moving rats increases acetylcholine (ACh) levels in the ventral hippocampus. It also increases levels of epinephrine, dopamine, and serotonin. The effects on neurotransmitter levels differ from those of donepezil (E2020), with Zanapezil showing a more selective increase in ACh and 5-HT. |
| Enzyme Assay |
The AChE inhibition is determined using a standard colorimetric assay. Rat cerebral cortex homogenates are incubated with varying concentrations of Zanapezil free base in a reaction buffer. The substrate acetylthiocholine and Ellman‘s reagent (DTNB) are added. The reaction proceeds for 15-30 min at 37degC, and the absorbance of the yellow thionitrobenzoate product is measured at 412 nm to calculate the IC50 for AChE inhibition.
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| Cell Assay |
Cell-based assays are not standard for AChE inhibitors, as the enzyme is soluble. However, functional cholinergic activity can be assessed in primary neuronal cultures or cholinergic cell lines (e.g., SN56 cells). Cells are treated with Zanapezil, and the accumulation of acetylcholine in the culture medium (in the presence of a choline uptake inhibitor) is measured by HPLC-ECD or a commercial choline/acetylcholine assay kit.
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| Animal Protocol |
Animal/Disease Models: Male Wistar rats 7 weeks in age (230-240 g)[2]
Doses: 5 and 10 mg/kg Route of Administration: Oral administration Experimental Results: Increased acetylcholine (ACh) level in the VH for 120 min. A standard in vivo protocol uses microdialysis in freely moving rats. Male Sprague-Dawley rats are implanted with a guide cannula in the ventral hippocampus. After recovery, a microdialysis probe is inserted, and artificial cerebrospinal fluid is perfused. Zanapezil (2 mg/kg) or vehicle is administered orally, and dialysate samples are collected every 20-30 minutes. Acetylcholine and monoamine levels in the dialysate are analyzed by HPLC-ECD. |
| ADME/Pharmacokinetics |
Zanapezil is orally active and shows potent AChE inhibition in the brain following systemic administration. In rat plasma, the drug is detected after oral administration, and its effects on neurotransmitter levels are sustained for hours. However, its development was discontinued due to a lack of a dose-dependent effect in clinical trials. No detailed PK parameters (t1/2, Cmax) are provided.
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| Toxicity/Toxicokinetics |
No detailed toxicological data is provided. As an AChE inhibitor, potential side effects are cholinergic in nature, including gastrointestinal disturbances (nausea, vomiting, diarrhea), bradycardia, and muscle cramps. The drug progressed to clinical trials, indicating an acceptable safety profile in early studies, though development was halted for efficacy, not safety, reasons.
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| References |
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| Additional Infomation |
Zanapezil belongs to the piperidine class of drugs. Zanapezil (TAK-147) is a selective acetylcholinesterase inhibitor currently under investigation for its potential as a treatment for Alzheimer's disease (AD). Drug Indications: For the treatment of dementia symptoms in patients with Alzheimer's disease. Mechanism of Action: Zanapezil improves cognitive function in dementia patients by inhibiting the degradation of the neurotransmitter acetylcholine, preventing a decrease in acetylcholine levels in the brain. It is expected to selectively act on the central nervous system, thereby reducing peripheral adverse reactions. Pharmacodynamics: Zanapezil was developed by Takeda Pharmaceutical Company as an acetylcholinesterase inhibitor for the treatment of dementia symptoms in patients with Alzheimer's disease. In May 2003, the company discontinued development of this compound because no dose-dependent effect was observed in trials.
Zanapezil (TAK-147) was a clinical-stage candidate developed by Takeda Pharmaceutical Company for the treatment of Alzheimer‘s disease. Its chemical structure is distinct from donepezil, another leading AChE inhibitor. The development of Zanapezil was discontinued due to a lack of a dose-dependent effect in clinical trials, making it an example of a candidate that failed despite promising preclinical data, thus serving as an important reference for understanding the requirements for successful CNS drug development. |
| Molecular Formula |
C25H32N2O
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| Molecular Weight |
376.53
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| Exact Mass |
376.251
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| CAS # |
142852-50-4
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| Related CAS # |
Zanapezil fumarate;263248-42-6
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| PubChem CID |
198752
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| Appearance |
White to light yellow solid powder
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| LogP |
5.385
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
479
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CCNC2=C(C1)C=CC(=C2)C(=O)CCC3CCN(CC3)CC4=CC=CC=C4
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| InChi Key |
PMBLXLOXUGVTGB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H32N2O/c28-25(23-11-10-22-8-4-5-15-26-24(22)18-23)12-9-20-13-16-27(17-14-20)19-21-6-2-1-3-7-21/h1-3,6-7,10-11,18,20,26H,4-5,8-9,12-17,19H2
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| Chemical Name |
3-(1-benzylpiperidin-4-yl)-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)propan-1-one
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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 | 2.6558 mL | 13.2792 mL | 26.5583 mL | |
| 5 mM | 0.5312 mL | 2.6558 mL | 5.3117 mL | |
| 10 mM | 0.2656 mL | 1.3279 mL | 2.6558 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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