GABAA receptor modulator-14
GABAA receptor modulator-14 is an orally active, blood-brain barrier permeable selective positive allosteric modulator (PAM) of extrasynaptic δ-containing GABAA receptors (α4β3δ subtype) with an EC50 of 0.8 μM. GABAA receptor modulator-14 selectively enhances tonic neuronal inhibition by potentiating GABA-evoked currents mediated by extrasynaptic δ-GABAARs, produces rapid sustained antidepressant effects, elevates slow-wave NREM sleep and shows no addiction liability in mice. GABAA receptor modulator-14 can be applied to major depressive disorder (MDD) and comorbid insomnia research.
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- CAS No.: 3103822-75-6
- Formula: C22H13F2N5O2S
- Molecular Weight:449.43
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
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Biological Activity
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δ-GABAA Receptor 0.8 μM (EC50) |
GABAA receptor modulator-14 (Compound 12i) (0.03-30 μM) exhibits potent positive allosteric modulation in Xenopus oocytes expressing human α4β3δ GABAARs according to concentration–response analysis[1].
GABAA receptor modulator-14 (10 μM; 5 s) produced a 950% enhancement of GABA-evoked currents with an EC50 of 0.8 μM in Xenopus oocytes expressing human α4β3δ GABAARs[1].
GABAA receptor modulator-14 (10 μM; 30 s) displays target specificity toward GABAARs in Xenopus oocytes[1].
GABAA receptor modulator-14 selectively binds the allosteric pocket of α4β3δ GABAARs via key interactions with β3-PHE289 to exert subtype-selective PAM activity in Xenopus laevis oocytes[1].
GABAA receptor modulator-14 (1 μM; 0-60 min) exhibits an elimination half-life (T1/2) of >186.4 min and an intrinsic clearance (CLint) of <7.4 μL/min/mg protein in mouse liver microsomes, indicating remarkably low hepatic clearance potential[1].
GABAA receptor modulator-14 (1 μM) shows moderate permeability and minimal efflux in Caco-2 monolayers with an efflux ratio of 1.21[1].
GABAA receptor modulator-14 (10 μM) shows negligible inhibition of hERG and hNaV1.5 cardiac channels in vitro patch-clamp tests, implying low cardiac toxic risk[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | Tmax | T1/2 | Cmax | MRT0-inf | AUClast | AUCinf | F | C0 | Vz | Vss |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 1 mg/kg | i.p. | 0.8 h | 13.3 h | 208 ng/mL | 23.8 h | 5882 ng/mL·h | 5901 ng/mL·h | 90 % | / | / | / |
| Mice[1] | 1 mg/kg | i.v. | / | 14.9 h | / | 27.4 h | 6488 ng/mL·h | 6531 ng/mL·h | / | 6756 ng/mL | 3.3 L/kg | 4.2 L/kg |
| Mice[1] | 1 mg/kg | p.o. | 8.0 h | 16.4 h | 92 ng/mL | 28.1 h | 3624 ng/mL·h | 3649 ng/mL·h | 56 % | / | / | / |
GABAA receptor modulator-14 (0.3-3 mg/kg; i.p.; single dose) exerts antidepressant-like activity mainly via GABAARs in male C57BL/6J or ICR mice[1].
GABAA receptor modulator-14 (0.3-3 mg/kg; i.p.; once every other day; for 5 days) displays dose-dependent antidepressant-like efficacy upon repeated dosing in C57BL/6J and ICR mice[1].
GABAA receptor modulator-14 (1 mg/kg; i.p.; once every 48 h; for 5 days) displays superior antidepressant potency in the TST relative to allopregnanolone in C57BL/6J mice subjected to 28-day CRS prior to compound administration[1].
GABAA receptor modulator-14 (1 mg/kg; i.p.; single dose) relies entirely on δ-subunit-containing extrasynaptic GABAARs to exert its antidepressant-like effects in C57BL/6J mice subjected to 28-day CRS prior to compound administration[1].
GABAA receptor modulator-14 (1 mg/kg; i.p.; single dose) improves sleep while preserving physiological sleep benefits and producing no REM-associated adverse effects in C57BL/6J mice with PCPA (HY-B1368)-induced insomnia[1].
GABAA receptor modulator-14 (1 mg/kg; i.p.; once daily; for 7 days) exhibits low abuse liability, conferring a unique advantage for long-term therapeutic application in male C57BL/6J mice[1].
GABAA receptor modulator-14 (1 mg/kg; p.o.; once daily; for 28 days) exerts sustained potent efficacy when given orally together with CRS modeling[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:7-9-week-old male C57BL/6N mice[1]
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Dosage:3 mg/kg
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Administration:i.p., single dose
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Result:Displayed high brain uptake and prolonged intracerebral residence.
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Animal Model:6-8-week-old male C57BL/6J or ICR mice[1]
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Dosage:0.3 mg/kg, 1 mg/kg, 3 mg/kg
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Administration:i.p., single dose
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Result:Significantly reduced immobility time at medium and high doses.
Lost ability to shorten immobility time when coadministered with the GABAAR antagonist bicuculline (BIC).
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Animal Model:6-8-week-old male C57BL/6J or ICR mice[1]
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Dosage:0.3 mg/kg, 1 mg/kg, 3 mg/kg
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Administration:i.p., once every other day, for 5 days
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Result:Exerted dose-dependent antidepressant-like effects after repeated administration in both C57BL/6J and ICR mice.
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Animal Model:6-8-week-old male C57BL/6J mice underwent 28-day CRS before compounds administration[1]
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Dosage:1 mg/kg
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Administration:i.p., once every 48 h, for 5 days
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Result:Produced stronger antidepressant effects in TST than allopregnanolone.
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Animal Model:6-8-week-old male C57BL/6J mice underwent 28-day CRS before compounds administration[1]
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Dosage:1 mg/kg
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Administration:i.p., single dose
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Result:Lost antidepressant-like activity in Gabrd−/− knockout mice.
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Animal Model:6-8-week-old male C57BL/6J mice exhibiting valid symptoms of insomnia following the PCPA insomnia model induction[1]
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Dosage:1 mg/kg
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Administration:i.p., single dose
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Result:Reversed PCPA-caused NREM sleep reduction.
Showed stronger NREM-promoting efficacy than THIP, allopregnanolone and fluoxetine.
Exerted no notable impact on REM sleep.
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Animal Model:6-8-week-old male C57BL/6J mice[1]
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Dosage:1 mg/kg
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Administration:i.p., once daily, for 7 days
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Result:Did not induce addiction-related behaviors in mice.
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Animal Model:6-8-week-old male C57BL/6J mice[1]
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Dosage:1 mg/kg
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Administration:p.o., once daily, for 28 days
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Result:Administered orally alongside CRS retained potent therapeutic efficacy.
Chemical Information
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CAS No. 3103822-75-6
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Molecular Weight 449.43
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Formula C22H13F2N5O2S
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SMILES
O=C1C2=C(N=C(N1C3=CC(F)=CC(F)=C3)C4=CC=CC=C4)N=C(C5=CN=C(N=C5)OC)S2
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
GABAA receptor modulator-14 Related Classifications
HY-184478 Related Classifications
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