Org 34167 (freebase)
Org 34167 freebase is a blood-brain barrier permeable HCN channel modulator. Org 34167 freebase possesses high Caco-2 cell permeability. Org 34167 freebase modulates HCN channel function to alter activation properties and suppress neuronal hyperexcitability. Org 34167 freebase induces tremors in mice at specific doses. Org 34167 freebase acts as a research tool for studies on developmental and epileptic encephalopathies as well as depression.
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- CAS No.: 198968-25-1
- Formule: C17H16N2O
- Masse moléculaire:264.32
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Protocole
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
Description
In Vitro
Org 34167 freebase restores voltage dependence and reduces cation leak in homomeric HCN1M305L channels, heterozygous HCN1WT+M305L channels, and heterozygous channels expressing five additional HCN1 DEE variants in Xenopus laevis oocytes[1].
Org 34167 freebase inhibits wild‑type human HCN1 channels expressed in Xenopus laevis oocytes via multiple mechanisms, including a dose‑dependent hyperpolarizing shift in the mid‑point voltage of activation (V0.5, IC50 = 331 μM), and a dose‑dependent change in effective valence (z, IC50 = 219 μM)[2].
Org 34167 freebase inhibits truncated human HCN1WT-Δ channels expressed in Xenopus laevis oocytes via mechanisms independent of the CNBD[2].
Org 34167 freebase modulates human HCN1 channel gating by altering the PD open-closed equilibrium (IC50 = 7.9 μM), weakening VSD-PD coupling (IC50 = 63 μM), and favoring inactive VSD states (IC50 = 316 μM)[2].
Org 34167 (compound 33) (0.1-1 mM; 4 h) freebase shows high permeability across Caco-2 cell monolayers with Papp,ab values of 1.42×10-5 cm/s at 1 mM and 1.25×10-5 cm/s at 0.1 mM, and permeability ratios < 2, indicating it is not a Pgp substrate in this system[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
In Vivo
Org 34167 freebase achieves good brain penetration in male Wistar rats, with a Cbrain/Cblood ratio of 1.00[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Hcn1M294L knock-in (heterozygous, male/female, postnatal day 60-99 for behavioral experiments; postnatal day 20-30 for ex vivo slice electrophysiology); wild-type littermates (male/female, postnatal day 60-99 for behavioral experiments; postnatal day 20-30 for ex vivo slice electrophysiology)[1]
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Dosage:1 mg/kg (ECoG); 2 mg/kg (ECoG, behavioral); 30 μM (ex vivo electrophysiology)
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Administration:i.p.; single dose (ECoG, behavioral); bath application (ex vivo electrophysiology)
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Result:Restored altered voltage dependence, reduced cation leak, and suppressed hyperexcitability in mutant HCN1 channels.
Normalized electrophysiological deficits and decreased epileptiform activity in Hcn1M294L mice.
Induced tremors at therapeutic doses while partially normalizing anxiety-related behaviors.
Differentially modulated wild-type and mutant HCN1-mediated neuronal excitability.
Chemical Information
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CAS No. 198968-25-1
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Masse moléculaire 264.32
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Formule C17H16N2O
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SMILES
N[C@H](C1=C(C=CC=C1)C2=NOC3=CC=CC=C23)CC=C
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocole
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Transepithelial/transendothelial electrical resistance assay
TEER measures electrical resistance across epithelial or endothelial monolayers cultured on permeable supports, and the readout reflects ionic conductance through the cell barrier, especially the paracellular pathway regulated by junctional integrity. TEER can be measured without destroying the monolayer and is commonly used before or during transport, permeability, barrier-disruption, and barrier-maturation experiments. TEER values are influenced by biological maturation and technical conditions; reported factors include temperature, medium formulation, passage number, electrode geometry, membrane properties, and junctional length during early monolayer maturation. Therefore, TEER should be interpreted with blank-insert subtraction, area normalization, repeated readings, and, when possible, orthogonal barrier readouts such as FITC-dextran flux or tight-junction staining.
Pureté et documentation
Références
[1]. Bleakley LE, et al. Org 34167 rescues voltage dependence of mutant channels and normalizes hyperexcitability in HCN1 epilepsy. Epilepsia. 2025;66(12):5082-5095. [Content Brief]
[2]. McKenzie CE, et al. The Potential Antidepressant Compound Org 34167 Modulates HCN Channels Via a Novel Mode of Action. Mol Pharmacol. 2023;104(2):62-72. [Content Brief]
[3]. Faassen F, et al. Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003;263(1-2):113-122. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Org 34167 (freebase) Related Classifications
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