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| Targets |
GABAA Receptor alpha2/alpha3 Subtypes and alpha1 Subtype. TPA-023B binds to the benzodiazepine site on GABAA receptors with high affinity: Ki = 0.73 nM for alpha2 subtype, 2 nM for alpha3 subtype, and 1.8 nM for alpha1 subtype. It acts as a partial agonist at alpha2/alpha3 subtypes (which are associated with anxiolytic effects) and as an antagonist at the alpha1 subtype (which is associated with sedation, ataxia, and tolerance). This unique functional profile dissociates anxiolytic efficacy from sedative side effects.
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| ln Vitro |
TPA-023B exhibits a high affinity for the human recombinant GABAA receptor's α5 isoform (Ki 1.1 nM), whereas its affinity for the isoforms that contain α4 and α6 is more than 1500 times lower (Ki > 1000 nM). Additionally, TPA-023B exhibits a high degree of affinity for native rat GABAA receptors in the frontal cortex, spinal cord, and cerebellum (Ki 0.32-0.99 nM) [1]. In cells expressing α1 isoform, TPA-023B inhibits chlordiazepoxide's capacity to increase GABA EC20-induced currents. To be more precise, 3 μM chlordiazepoxide increased GABA EC20 currents by 105%; however, this impact was only 8% when 100 nM TPA-023B was present [1].
TPA-023B binds with high affinity to human GABAA receptors: Ki = 0.73 nM for alpha2 subtype, 2 nM for alpha3 subtype, and 1.8 nM for alpha1 subtype. The compound is an imidazotriazine-based benzodiazepine site ligand. It does not exhibit the sedative, myorelaxant, or tolerance-inducing effects of full non-selective agonists such as diazepam or alprazolam. TPA-023B shows anxiolytic-like activity in preclinical models with a much wider therapeutic index compared to conventional benzodiazepines. |
| ln Vivo |
Using an in vivo [3H]flumazenil binding assay, TPA-023B produced dosage- and time-dependent occupancy of rat brain GABAA receptors, with 50% occupancy matching to the relevant dose and plasma drug concentration of 0.09 mg/kg and 19 ng/ml[1]. The highest dose (10 mg/kg) of TPA-023B corresponds to an occupancy rate greater than 99% in rodents and primates (squirrel monkeys) with ataxia and/or muscle flaccidity, but not in rodents or in primates with conditioned drinking inhibition, fear-potentiated startle, elevated plus maze, or conditioned emotional responses [1].
TPA-023B exhibits non-sedating anxiolytic-like properties in rodent models of anxiety, including the elevated plus maze, Vogel conflict test (punished drinking), and fear-potentiated startle. In these models, TPA-023B (0.3-10 mg/kg orally) significantly increases punished responding and open arm exploration without causing sedation, muscle relaxation, or motor impairment (rotarod performance). Unlike diazepam, TPA-023B does not produce tolerance after repeated dosing, nor does it show significant withdrawal effects upon discontinuation. It also lacks abuse potential in self-administration studies. |
| Enzyme Assay |
Radioligand binding assays for GABAA receptor subtypes are performed using membrane preparations from CHO or HEK-293 cells stably expressing human recombinant alpha1beta3gamma2, alpha2beta3gamma2, or alpha3beta3gamma2 GABAA receptors. Membranes (50-100 microg protein) are incubated with [3H]flumazenil (0.5-1 nM) as the radioligand and varying concentrations of TPA-023B (0.01-1000 nM) in 50 mM Tris-citrate buffer (pH 7.4) containing 150 mM NaCl for 60 minutes at 4degC. Nonspecific binding is determined with 10 microM diazepam. Bound and free radioligands are separated by filtration through GF/B filters pre-soaked in 0.3% PEI. Bound radioactivity is measured by liquid scintillation. Ki values are calculated using the Cheng-Prusoff equation.
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| Cell Assay |
Not applicable (GABAA receptor functional activity is assessed in electrophysiology assays, not in conventional cell viability assays). For functional studies, CHO or HEK-293 cells expressing alpha1beta3gamma2, alpha2beta3gamma2, or alpha3beta3gamma2 GABAA receptors are used. GABA-evoked currents are recorded using whole-cell patch-clamp electrophysiology. TPA-023B (0.1-1000 nM) is co-applied with a submaximal concentration of GABA (typically EC20, 0.1-1 microM). The potentiation of GABA-evoked current is measured. The compound acts as a partial agonist at alpha2/alpha3 (maximal potentiation ~30-50% of that of diazepam) and as an antagonist at alpha1 (blocks diazepam potentiation).
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| Animal Protocol |
Male Sprague-Dawley rats (200-250 g, n=8-12 per group) are used for the elevated plus maze test. TPA-023B (0.3-10 mg/kg) or vehicle (0.5% methylcellulose) is administered orally 60-90 minutes before testing. The rat is placed in the center of a plus-shaped maze (two open arms, two closed arms) and allowed to explore for 5 minutes. The number of entries and time spent in the open arms are recorded. Anxiolytic-like activity is indicated by increased open arm exploration. For the rotarod test (to assess sedation/motor impairment), rats are placed on a rotating rod (4-16 rpm accelerating), and the latency to fall is measured. TPA-023B does not reduce rotarod performance even at high doses (100 mg/kg).
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| ADME/Pharmacokinetics |
TPA-023B is well absorbed orally (bioavailability ~50-70% in rodents) and crosses the blood-brain barrier readily. Following oral administration (1-10 mg/kg) in rats, peak plasma concentrations (Cmax) are reached within 1-2 hours (Tmax), with a terminal half-life of 3-6 hours. Brain concentrations of TPA-023B exceed plasma concentrations, consistent with its CNS target. The compound is metabolized primarily by CYP3A4 and is eliminated in urine and feces. No active metabolites have been identified.
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| Toxicity/Toxicokinetics |
TPA-023B is a research compound; clinical development has been explored but not completed. In preclinical safety studies, the compound has a wide safety margin (therapeutic index > 100). At doses up to 100 mg/kg (oral) in rodents, no significant sedation, motor impairment, respiratory depression, or cardiovascular effects were observed. Common adverse effects at supratherapeutic doses include mild gastrointestinal disturbances. No hepatotoxicity or nephrotoxicity has been reported. TPA-023B does not produce physical dependence or withdrawal symptoms.
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| References | |
| Additional Infomation |
TPA-023B is a GABAA receptor subtype-selective ligand that discriminates between the alpha1, alpha2, and alpha3 subunits. The alpha2 and alpha3 subtypes are thought to mediate anxiolytic effects, while the alpha1 subtype mediates sedation, ataxia, and tolerance. TPA-023B is a chemical probe for studying the role of alpha2/alpha3 vs. alpha1 GABAA receptors in anxiety, cognition, and the side effects of benzodiazepines. It is not an FDA-approved drug but has been investigated in clinical trials for generalized anxiety disorder (GAD). The compound is for research use only.
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| Molecular Formula |
C₂₁H₁₅F₂N₅O
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|---|---|
| Molecular Weight |
391.37
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| Exact Mass |
391.124
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| CAS # |
425377-76-0
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| PubChem CID |
9865233
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| Appearance |
Light yellow to green yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.658
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| LogP |
1.36
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
29
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| Complexity |
640
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
PCZLQMGFNUNVOM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H15F2N5O/c1-21(2,29)18-11-26-28-17(10-25-20(28)27-18)12-6-7-15(22)14(8-12)19-13(9-24)4-3-5-16(19)23/h3-8,10-11,29H,1-2H3
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| Chemical Name |
3-fluoro-2-[2-fluoro-5-[3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]phenyl]benzonitrile
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| Synonyms |
TPA023B; TPA 023B
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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) |
DMSO : ~100 mg/mL (~255.51 mM)
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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 | 2.5551 mL | 12.7756 mL | 25.5513 mL | |
| 5 mM | 0.5110 mL | 2.5551 mL | 5.1103 mL | |
| 10 mM | 0.2555 mL | 1.2776 mL | 2.5551 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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