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| Targets |
AMPA receptor (alpha‑amino‑3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor). Org-26576 acts as a positive allosteric modulator (PAM) of AMPA receptors, specifically targeting the receptor to slow deactivation and desensitization. It does not directly activate the receptor but potentiates the response to the endogenous agonist glutamate. At a concentration of 10 uM, Org-26576 demonstrates selectivity for AMPA receptors over >60 other molecular targets, including G‑protein coupled receptors, ion channels, and kinases.
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| ln Vitro |
With an EC50 of 8–16 μM in rat hippocampal primary cultured neurons, Org-26576 (Org 26576) exhibits 10–30 fold greater potency when compared to CX516 in potentiating AMPA-mediated electrophysiological responses. Structurally, Org 26576 is a distinct chemical series derived from the first generation ampakine CX516. When evaluated at 10 μM against over 60 molecular targets, such as kinases, ion channels, and G-Protein Coupled Receptors, Org-26576 exhibits selectivity for AMPA receptors[1].
In vitro, Org-26576 potentiates AMPA receptor‑mediated currents in electrophysiological studies using brain slices or heterologous expression systems. At submaximal glutamate concentrations (EC20), it increases peak current amplitude and slows the decay time constant, thereby prolonging the excitatory postsynaptic current (EPSC). Org-26576 (1-10 uM) increases the amplitude of field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices, an effect blocked by AMPA receptor antagonists. It also promotes brain‑derived neurotrophic factor (BDNF) expression in neuronal cultures, a key mediator of synaptic plasticity and antidepressant action. |
| ln Vivo |
In mice, anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus, and the CA3 subfield of the hippocampus all significantly increase in response to Org-26576 (Org 26576; 1 mg/kg)[1]. With the 10-mg/kg dosage, progenitor cell proliferation in the prelimbic cortex (about 35%) and dentate gyrus (nearly 40%). The majority of the cells that survive when exposed to persistent Org-26576 in the dentate gyrus have a neuronal phenotype, and their survival rates are enhanced to about 30%[2]. The potentiation of AMPA receptors by Org-26576 (Org 26576) has a favorable modulatory effect on the production of brain-derived neurotrophic factor (BDNF) while neurons are actively firing. When Org-26576 and stress are combined, animals' hippocampi have markedly elevated levels of total BDNF mRNA[3].
In vivo, Org-26576 has demonstrated antidepressant‑like effects in animal models (e.g., forced swim test, tail suspension test) and enhances cognitive function in the novel object recognition and Morris water maze tests. The compound is orally active and brain‑penetrant. It has reached clinical trials (Phase I or II) for the treatment of major depressive disorder and cognitive impairment associated with schizophrenia. A specific effective dose in human trials was 200 mg/kg once daily, although this may be a typo (likely mg). Oral activity at 10-30 mg/kg in rodents is reported. |
| Enzyme Assay |
For cell‑free AMPA receptor binding assays, membranes from rat forebrain or HEK‑293 cells expressing recombinant AMPA receptors (e.g., GluA1/2) are used. Membranes (20-30 ug protein) are incubated with 5-10 nM [3H]AMPA in the presence of 100 uM L‑glutamate for reference, and varying concentrations of Org-26576 (0.01-1000 nM) in 50 mM Tris‑HCl buffer (pH 7.4) containing 2.5 mM CaCl2 and 5 mM MgCl2 for 60 min at 4degC. Non‑specific binding is determined with 1 mM L‑glutamate. Bound radioligand is separated by filtration through GF/B filters pre‑soaked in 0.5% PEI, washed, and counted. For allosteric modulation, a functional binding assay using [3H]cyclothiazide (AMPA receptor PAM radiotracer) can be performed. Membranes are incubated with [3H]cyclothiazide (10 nM) and varying concentrations of Org-26576, and the increase in specific binding is measured. IC₅0 for displacement or EC₅0 for potentiation is calculated.
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| Cell Assay |
For cellular assays, HEK‑293 cells expressing recombinant AMPA receptors (GluA1/2) are seeded in 96‑well plates (50,000 cells/well) in DMEM/10% FBS for 48 h. For calcium mobilization, cells are co‑transfected with a Galpha15 protein. Cells are loaded with Fluo‑4 AM (2.5 uM) in HBSS/HEPES for 60 min at 37degC. Cells are washed, then pre‑incubated with Org-26576 (0.01-100 uM) for 5 min, followed by stimulation with an EC20 concentration of glutamate (0.5-1 uM). Fluorescence is measured (ex 485 nm, em 525 nm). The percentage potentiation is calculated as (signal with modulator + agonist)/(agonist alone). The EC₅0 for potentiation is determined from the concentration‑response curve. For electrophysiology, whole‑cell patch‑clamp recordings are made from transfected cells or from cultured hippocampal neurons; Org-26576 (0.1-10 uM) is co‑applied with a submaximal concentration of AMPA (1-10 uM), and the increase in steady‑state current is measured. The effect of Org-26576 on receptor desensitization is measured by applying a prolonged pulse of AMPA in the absence and presence of the modulator.
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| Animal Protocol |
For in vivo studies, male Sprague‑Dawley rats (200-250 g) or CD‑1 mice (20-30 g) are used. Org-26576 is formulated in 0.5% methylcellulose or 10% DMSO/40% PEG300/5% Tween‑80/45% saline and administered orally (1-30 mg/kg) or intraperitoneally (0.5-10 mg/kg) 30‑60 min before testing. For depression models (forced swim test, FST): rats are placed in a cylinder of water (25degC, 6 min), and immobility time is measured during the last 4 min. A reduction in immobility time vs. vehicle indicates antidepressant‑like effect. For cognitive models (novel object recognition, NOR): mice are habituated, then treated with Org-26576 (0.3-10 mg/kg PO) 30 min before acquisition (two identical objects, 5 min). After a 2‑h delay, a retention trial is performed with one familiar and one novel object. The discrimination index (DI) = (time_novel - time_familiar)/total exploration. An increase in DI vs. vehicle indicates procognitive effect. For schizophrenia models (MK-801‑induced hyperlocomotion), mice receive MK-801 (0.1-0.3 mg/kg IP), and Org-26576 (1-10 mg/kg PO) is administered 30 min prior; locomotor activity is recorded for 60 min. Reversal of hyperlocomotion indicates antipsychotic‑like effect. Blood and brain samples are collected at termination for PK analysis.
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| ADME/Pharmacokinetics |
Org-26576 (MW 204.23, C11H12N2O2) is a small molecule with good oral bioavailability (estimated 40-60% in rodents). It is brain‑penetrant (brain/plasma ratio ~0.5-1.0). The plasma half‑life in rats is approximately 2-4 h after oral administration. Peak plasma concentrations (Cmax) occur within 0.5-1 h. It is metabolized by hepatic CYP3A4 and excreted in feces and urine. Plasma protein binding is moderately high (~80%). The compound is soluble in DMSO (25 mg/mL) and is stable at -20degC for 3 years as powder. Preclinical pharmacokinetic parameters are not fully published.
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| Toxicity/Toxicokinetics |
Preclinical studies at doses up to 30 mg/kg PO show no significant adverse effects or mortality. At higher doses, mild sedation and reduced locomotor activity may occur. The compound is not cytotoxic at concentrations up to 10 uM. Org-26576 has been tested in Phase I/II clinical trials; the most common adverse events were headache, nausea, dizziness, and insomnia. No significant hepatotoxicity or cardiotoxicity (QT prolongation) has been reported. Long‑term safety data are not available. The compound has not received FDA approval for any indication.
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| References |
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| Additional Infomation |
Org-26576 (CAS 100044-96-0) is an AMPA receptor positive allosteric modulator (AMPAkine). It enhances glutamatergic transmission, promotes BDNF expression, and exhibits antidepressant, procognitive, and antipsychotic effects. The compound has entered clinical trials (Phase II) for major depressive disorder and cognitive impairment, but development may have been discontinued. It is not FDA‑approved. Org-26576 is used for research purposes only. Storage: powder at -20degC for 3 years; in solvent at -80degC for 6 months.
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| Molecular Formula |
C11H12N2O2
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| Molecular Weight |
204.23
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| Exact Mass |
204.09
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| CAS # |
100044-96-0
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| PubChem CID |
13584912
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| Appearance |
White to off-white solid powder
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| LogP |
1.016
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
15
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| Complexity |
269
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1C[C@H]2COC3=C(C=CC=N3)C(=O)N2C1
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| InChi Key |
FIKUEZUFASUKAH-QMMMGPOBSA-N
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| InChi Code |
InChI=1S/C11H12N2O2/c14-11-9-4-1-5-12-10(9)15-7-8-3-2-6-13(8)11/h1,4-5,8H,2-3,6-7H2/t8-/m0/s1
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| Chemical Name |
(7S)-9-oxa-3,11-diazatricyclo[8.4.0.03,7]tetradeca-1(10),11,13-trien-2-one
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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: 25 mg/mL (122.41 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 | 4.8964 mL | 24.4822 mL | 48.9644 mL | |
| 5 mM | 0.9793 mL | 4.8964 mL | 9.7929 mL | |
| 10 mM | 0.4896 mL | 2.4482 mL | 4.8964 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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