| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 100mg | |||
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| Targets |
GABAA receptor α2/α3 subtypes. TPA023 is a selective agonist of GABAA α2/α3 with Ki values of 0.19-0.41 nM. It has Kd values of 0.92, 1.05 and 0.58 nM for α1-, α2-, α3-, and α5-containing human receptors. The compound acts as a partial agonist at α2/α3 and as a silent antagonist at α1/α5.
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| ln Vitro |
In vitro, TPA023 shows high affinity for GABAA α2/α3 subtypes with Ki values of 0.19-0.41 nM. The compound has Kd values of 0.92, 1.05 and 0.58 nM for α1-, α2-, α3-, and α5-containing human receptors. It exhibits subtype-selective modulation of GABA-induced chloride currents in recombinant receptor systems.
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| ln Vivo |
When TPA023 was given orally to rats, excellent receptor occupancy was observed. TPA023 was administered at a dose of 0.42 mg/kg, which resulted in a 50% occupancy of GABAA receptors in the rat brain. The equivalent plasma concentration was 25 ng/mL. In a mouse model of pentylenetetrazole-induced seizures, TPA023 shown efficacy as well, offering complete protection against seizures (84% occupancy) at a dose of 10 mg/kg ip, with an ED50 of 0.19-0.41 nM, as well as protection against cataleptic convulsions (1.4 mg/kg). kg ip) is equivalent to roughly 50% occupancy. Rats treated orally with TPA023 (3 mg/kg, dissolved in 0.5% methylcellulose) exhibit anxiolytic-like effects [1]. TPA023 (0.7, 2.0, and 5 mg/kg, orally) prevents ketamine's cognitive impairment in rhesus monkeys, but it has no effect on behavioral symptoms [2].
In vivo, TPA023 displays excellent receptor occupancy when administered orally to rats. A dose of 0.42 mg/kg resulted in 50% occupancy of GABAA receptors in the rat brain, with an equivalent plasma concentration of 25 ng/mL. In a mouse model of pentylenetetrazole-induced seizures, TPA023 offered complete protection (84% occupancy) at 10 mg/kg i.p.. Rats treated orally with TPA023 (3 mg/kg) exhibit anxiolytic-like effects. TPA023 (0.7, 2.0, and 5 mg/kg, orally) prevents ketamine's cognitive impairment in rhesus monkeys. |
| Enzyme Assay |
Non-cell receptor binding assays are performed using membrane preparations from cells expressing human GABAA receptor subtypes (α1β3γ2, α2β3γ2, α3β3γ2, α5β3γ2). Radioligand binding studies are conducted using [³H]flumazenil as a tracer. Membranes are incubated with the radioligand and varying concentrations of TPA023 (0.001-100 nM). Nonspecific binding is determined with excess diazepam. After incubation at 4°C for 60-90 minutes, filtration and scintillation counting are performed. Ki and Kd values are calculated from competition curves.
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| Cell Assay |
Cellular assays are performed using HEK-293 or CHO cells transfected with GABAA receptor subunit combinations. Whole-cell patch-clamp electrophysiology is used to record GABA-induced chloride currents in the presence of TPA023 at concentrations ranging from 0.01-100 nM. The potentiation of submaximal GABA responses is measured to determine the EC₅₀ and efficacy. Alternatively, FLIPR-based membrane potential assays are used for high-throughput functional characterization.
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| Animal Protocol |
In vivo animal studies are conducted in rodent models of anxiety (elevated plus maze, light-dark box) and seizure (pentylenetetrazole-induced seizures). TPA023 is administered orally or intraperitoneally. Receptor occupancy is measured by ex vivo [³H]flumazenil binding. For primate studies, TPA023 is administered orally to rhesus monkeys and cognitive performance is assessed. Doses range from 0.42-10 mg/kg depending on the species and endpoint.
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| ADME/Pharmacokinetics |
Metabolism / Metabolites
Tpa-023's known human metabolites include 2-[6-[(2-ethyl-1,2,4-triazol-3-yl)methoxy]-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-7-yl]-2-methylprop-1-ol and 6-((1H-1,2,4-triazol-3-yl)methoxy)-7-tert-butyl-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine. TPA023 is orally active with good bioavailability. Following oral administration in rats, a dose of 0.42 mg/kg resulted in 50% receptor occupancy with a plasma concentration of 25 ng/mL. Known human metabolites include 2-[6-[(2-ethyl-1,2,4-triazol-3-yl)methoxy]-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-7-yl]-2-methylprop-1-ol. The compound is metabolized by hepatic enzymes. |
| Toxicity/Toxicokinetics |
In preclinical studies, TPA023 shows no sedative effects even at 50× the effective anxiolytic dose. In human trials on healthy volunteers, TPA-023 was comparable to lorazepam but had much fewer side effects on cognition, memory, alertness, or coordination. No significant organ-specific toxicity has been reported at therapeutic doses.
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| References |
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| Additional Infomation |
MK-0777 has been used in research trials to treat schizophrenia, anxiety disorders, and generalized anxiety disorder.
TPA023 (MK-0777) was developed as an anxiolytic agent with a subtype-selective profile at GABAA receptors. Its selectivity for α2/α3 over α1/α5 subtypes was designed to provide anxiolytic and anticonvulsant effects without sedation. MK-0777 has been used in research trials to treat schizophrenia, anxiety disorders, and generalized anxiety disorder. The compound is not approved for clinical use and is available for research purposes only. |
| Molecular Formula |
C20H22FN7O
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| Molecular Weight |
395.4424
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| Exact Mass |
395.187
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| CAS # |
252977-51-8
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| PubChem CID |
9908684
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| Appearance |
White to off-white solid powder
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| LogP |
3.418
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
547
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QKIWQBLNTSQOLY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H22FN7O/c1-5-27-17(22-12-23-27)11-29-19-14(20(2,3)4)10-16-24-25-18(28(16)26-19)13-8-6-7-9-15(13)21/h6-10,12H,5,11H2,1-4H3
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| Chemical Name |
7-tert-butyl-6-[(2-ethyl-1,2,4-triazol-3-yl)methoxy]-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine
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| Synonyms |
TPA 023; TPA-023; TPA023
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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 | 2.5288 mL | 12.6441 mL | 25.2883 mL | |
| 5 mM | 0.5058 mL | 2.5288 mL | 5.0577 mL | |
| 10 mM | 0.2529 mL | 1.2644 mL | 2.5288 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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