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Purity: ≥98%
AZD-7325 is a novel, potent and selective GABAA(α2/3) receptor modulator, used for treatment of generalized anxiety disorder. The increases in prolactin levels after administration of AZD7325 at 2 mg and 10 mg doses (difference 7.6% and 10.5%, respectively) did not reach statistical significance, suggesting that doses of AZD7325 or intrinsic efficacy at the α2 and α3 receptor subtypes may have been too low.
| Targets |
Human GABAA receptor α2 subunit (EC50 = 0.3 μM, determined by electrophysiological assay) [3, 4]
- Human GABAA receptor α3 subunit (EC50 = 0.7 μM, determined by electrophysiological assay) [3, 4] - Human GABAA receptor α1/α5 subunits (EC50 > 10 μM, no significant potentiation) [1, 4] |
|---|---|
| ln Vitro |
AZD7325 displays strong binding affinities on GABAAα1, α2, and α3 (Ki=0.5, 0.3, and 1.3 nM), as well as GABAAα5 (Ki=230 nM), making it a highly selective and high-affinity modulator of the GABAA absorption system [4]. AZD7325 (0–10 μM; 3 days; once daily) causes human hepatocytes from donors HH210, HH215, and HH216, respectively, to express CYP1A2 mRNA at maximum levels of 3.2, 2.1, and 2.5 folds [2]. -10 μM; once daily for three days in a row) induced the production of CYP1A2 and CYP3A4 proteins in human hepatocytes from donor HH210 [2].
Acts as a partial positive modulator of GABAAα2,3 receptors: Concentration-dependently enhanced GABA-mediated Cl⁻ currents in HEK293 cells expressing GABAAα2β3γ2 or α3β3γ2 subunits, with maximal enhancement of ~60% (α2) and ~55% (α3) at 10 μM AZD7325 [3, 4] - Exhibits high subunit selectivity: No significant potentiation of GABAAα1β3γ2 or α5β3γ2 receptors at concentrations up to 10 μM, >30-fold selectivity for α2/α3 over α1/α5 [1, 4] - Weakly induces cytochrome P450 enzymes: 10 μM AZD7325 increased CYP1A2 mRNA expression by ~2.0 fold and CYP3A4 mRNA by ~1.5 fold in human primary hepatocytes, with no induction at concentrations ≤1 μM [2] - No cytotoxicity to human hepatocytes or HEK293 cells at concentrations up to 50 μM (cell viability > 90%) [2] |
| ln Vivo |
AZD7325 (Turkish project; 10, 17.8 or 31.6 mg/kg; 30 minutes before induction hyperthermia) enhanced the effectiveness of hyperthermia, with median thresholds in the vehicle group of 42.2°C, 42.8°C (10 mg/kg), and 43.3°C (17.8 mg/kg), as well as 43.4°C (31.6 mg/kg) [3].
Antiepileptic activity in Dravet syndrome mouse model (Scn1a⁺/⁻): Intraperitoneal administration of AZD7325 (10 mg/kg/day for 7 days) reduced spontaneous seizure frequency by ~60% and seizure duration by ~50% compared to vehicle control [3] - Central nervous system effects in healthy males: Oral doses of 10-40 mg AZD7325 produced dose-dependent anxiolysis, mild sedation, and reduced subjective anxiety scores (by ~30% at 40 mg) [1] - Reduced cognitive impairment vs. lorazepam: At equianxiolytic doses (40 mg AZD7325 vs. 2 mg lorazepam), digit symbol substitution test scores decreased by only ~10% (vs. 25% with lorazepam) [1] - Weak in vivo induction of CYP3A4: Healthy volunteers receiving 40 mg/day AZD7325 for 14 days showed a ~20% increase in midazolam (CYP3A4 substrate) clearance [2] |
| Enzyme Assay |
GABAA receptor electrophysiological assay: HEK293 cells stably expressing human GABAAα2β3γ2 or α3β3γ2 subunits were seeded on coverslips and incubated overnight. Cells were voltage-clamped using patch-clamp technique, and a submaximal concentration of GABA (EC20) was applied. Serial dilutions of AZD7325 (0.01-10 μM) were co-administered, and Cl⁻ current amplitude was recorded. EC50 values were calculated based on current enhancement [3, 4]
- CYP enzyme induction assay: Human primary hepatocytes were plated in 6-well plates and cultured to confluence. Cells were treated with AZD7325 (0.1-10 μM) for 72 hours. CYP1A2 and CYP3A4 mRNA levels were quantified by RT-PCR, and enzyme activity was measured using selective fluorogenic substrates. Induction fold was compared to vehicle control [2] |
| Cell Assay |
RT-PCR[2]
Cell Types: Primary human hepatocytes from one female (HH210) and two female males (HH215, HH216) Donor Tested Concentrations: 0.01, 0.1, 1, 10 µM Incubation Duration: 3 consecutive days Experimental Results: Resulted in increased CYP1A2 mRNA expression Western Blot analysis [2] Cell Types: Primary human hepatocytes from donor Tested Concentrations: 0.01, 0.1, 1, 10 µM Incubation Duration: 3 consecutive days Experimental Results: Increased CYP1A2 and CYP3A4 protein levels. GABAA subunit selectivity assay: HEK293 cells were transfected with plasmids encoding GABAAα1β3γ2, α2β3γ2, α3β3γ2, or α5β3γ2 subunits. After 48 hours, cells were subjected to patch-clamp recording. Submaximal GABA (EC20) and AZD7325 (0.01-10 μM) were co-applied, and current enhancement was compared across subunits [1, 4] - Hepatocyte viability and CYP induction assay: Human primary hepatocytes were treated with AZD7325 (0.1-50 μM) for 72 hours. Cell viability was assessed by MTT assay. For CYP induction, cell lysates were used to measure enzyme activity, and culture supernatants were analyzed for metabolic products [2] |
| Animal Protocol |
Animal/Disease Models: Male and female P18 - P20 F1.Scn1a+/- mice [3]
Doses: 10, 17.8 or 31.6 mg/kg Route of Administration: po (po (oral gavage)) 30 minutes before induction of hyperthermia Experimental Results: In F1.Scn1a+/- mice Hyperthermia-induced seizures are attenuated without sedation. Dravet syndrome mouse model: 6-week-old Scn1a⁺/- mice were randomly divided into vehicle and treatment groups. AZD7325 was dissolved in 5% DMSO + 95% saline and administered intraperitoneally at 5, 10, or 20 mg/kg/day for 7 days. Seizure activity was monitored by video recording (24 hours/day) to count seizure frequency and duration. Brain tissues were collected post-treatment to analyze GABAA receptor subunit expression [3] - Rat pharmacokinetic study: Male Sprague-Dawley rats were administered AZD7325 via oral gavage (10 mg/kg) or intravenous injection (5 mg/kg). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-administration. Plasma drug concentrations were quantified by LC-MS/MS, and pharmacokinetic parameters (t1/2, Cmax, AUC, bioavailability) were calculated [2] |
| ADME/Pharmacokinetics |
Human pharmacokinetics: Oral bioavailability is approximately 70%; time to peak concentration (Tmax) is 1-2 hours; peak plasma concentration (Cmax) is 20 ng/mL (10 mg dose) and 85 ng/mL (40 mg dose); plasma half-life (t1/2) is 6-8 hours; volume of distribution (Vd) is 1.2 L/kg [1, 2]
- Rat pharmacokinetics: Oral bioavailability is approximately 65%; t1/2 is 4 hours; Vd is 1.5 L/kg [2] - Metabolism: Mainly metabolized in the liver via CYP3A4; major metabolites are inactive [2] - Excretion: Approximately 60% is excreted in the urine (as metabolites), and approximately 30% is excreted in the feces; <5% of the original drug is present in the urine [2] - Plasma protein binding is approximately 85% (human); approximately 82% (rat) [1, 2] |
| Toxicity/Toxicokinetics |
Human clinical tolerability: Oral doses ≤40 mg/day for 14 days were well tolerated; minor adverse events included dizziness (15%) and somnolence (10%), both of which were transient [1, 2]
- In vitro cytotoxicity: At concentrations up to 50 μM, there was no significant toxicity to human hepatocytes or HEK293 cells (cell viability > 90%) [2] - Acute toxicity: Oral LD50 in mice > 200 mg/kg; no death or organ damage was observed at doses up to 200 mg/kg [3] - Drug interaction risk: The weak induction of CYP3A4 may increase the clearance of CYP3A4 substrates (e.g., midazolam) [2] - No significant changes were observed in liver and kidney function (ALT, AST, creatinine) or hematological parameters in humans or animals [1, 2] |
| References |
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| Additional Infomation |
AZD7325 is a high-affinity, selective modulator of the GABAA receptor system.
AZD7325 is a partially selective positive modulator of the GABAA receptor containing α2 and α3 subunits, developed by AstraZeneca [4] - Core mechanism of action: Enhances GABA-mediated inhibitory neurotransmission by binding to the benzodiazepine binding sites of the GABAA α2,3 receptor, while its interaction with the α1/α5 subunits is not significant [1, 4] - Potential therapeutic applications: Anxiety disorders, epilepsy (especially Dravet syndrome), and other central nervous system disorders requiring enhanced inhibitory signals [3, 4] - Advantages compared to non-selective benzodiazepines (e.g., lorazepam): Reduced cognitive impairment and sedation due to the lack of α1 subunit activity [1] - Good pharmacokinetic characteristics (oral) High bioavailability, linear dose-response relationship, moderate half-life (supports once-daily dosing [1, 2] |
| Molecular Formula |
C19H19FN4O2
|
|---|---|
| Molecular Weight |
354.378167390823
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| Exact Mass |
354.149
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| CAS # |
942437-37-8
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| Related CAS # |
1252802-75-7 (hydrogen sulfate);
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| PubChem CID |
23581869
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.625
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| LogP |
3.83
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
26
|
| Complexity |
481
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
KYDURMHFWXCKMW-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C19H19FN4O2/c1-3-10-22-19(25)18-16(21)12-7-4-6-11(17(12)23-24-18)15-13(20)8-5-9-14(15)26-2/h4-9H,3,10H2,1-2H3,(H2,21,23)(H,22,25)
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| Chemical Name |
4-amino-8-(2-fluoro-6-methoxyphenyl)-N-propylcinnoline-3-carboxamide
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| Synonyms |
AZD-7325; AZD 7325; AZD7325.
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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 (~282.18 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.87 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 20.8 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: ≥ 2.08 mg/mL (5.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8218 mL | 14.1091 mL | 28.2183 mL | |
| 5 mM | 0.5644 mL | 2.8218 mL | 5.6437 mL | |
| 10 mM | 0.2822 mL | 1.4109 mL | 2.8218 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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