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Purity: ≥98%
GNE-8324 (GNE8324) is a novel, potent and selective PAM (Positive Allosteric Modulators) of NMDA receptor. NMDA Receptors (NMDARs) play key roles in synaptic physiology and NMDAR hypofunction has been implicated in various neurological conditions. In recent years an increasing number of positive allosteric modulators (PAMs) of NMDARs have been discovered and characterized. These diverse PAM classes vary not only in their binding sites and GluN2 subunit selectivity profiles, but also in the nature of their impacts on channel function. Major differences exist in the degree of slowing of channel deactivation and shifting of apparent agonist affinity between different classes of PAMs.
| Targets |
The target of GNE-8324 is the N-methyl-D-aspartate receptor (NMDAR), specifically the GluN2A subunit [1] [2]
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| ln Vitro |
GNE-8324 and the GluN2A NMDAR glutamate binding site have a reciprocal allosteric relationship that enables glutamate binding to increase GNE-8324 binding and vice versa. Selective enhancement of NMDARs with GluN2A subunits is seen by GNE-8324. Consequently, the occupancy of glutamate sites is critical for the potentiating effect of GNE-8324, and binding of GNE-8324 to glutamate-bound NMDARs is enhanced relative to glutamate-free NMDARs [1].
GNE-8324 acts as a GluN2A-selective positive allosteric modulator. In in vitro studies using brain slices, it selectively enhances NMDAR-mediated synaptic responses in inhibitory neurons (e.g., parvalbumin-positive interneurons) during low-frequency stimulation, but has no significant effect on excitatory neurons. A reciprocal allosteric interaction exists between GNE-8324 and glutamate at GluN2A NMDARs: glutamate binding enhances the affinity of GNE-8324 for the receptor, and vice versa [1] Long-term treatment with GNE-8324 (or its derivative M-8324) in cultured inhibitory neurons leads to persistent enhancement of NMDAR function, accompanied by upregulation of genes related to potassium channels and cell adhesion molecules, which modulates neuronal excitability and synaptic connectivity [2] |
| ln Vivo |
The derivative of GNE-8324, M-8324, when acutely administered to mice, enhances the activity of inhibitory neurons in vivo, reduces the excitatory/inhibitory (E/I) ratio in neural circuits, and improves sensory function as measured by behavioral assays. Long-term administration of M-8324 does not significantly affect cell cycle progression or apoptosis in brain tissues, indicating a favorable safety profile [2]
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| Cell Assay |
For electrophysiological recordings, brain slices containing inhibitory and excitatory neurons are prepared. GNE-8324 is applied to the bath solution at specified concentrations. Low-frequency stimulation is delivered to synaptic inputs, and NMDAR-mediated currents (e.g., EPSCs) are recorded using patch-clamp techniques to compare responses between inhibitory and excitatory neurons [1]
In cultured inhibitory neurons, cells are treated with GNE-8324 (or M-8324) for extended periods (days). Gene expression changes are analyzed via PCR, and protein levels of potassium channels and cell adhesion molecules are measured using western blotting. Neuronal excitability is assessed by recording action potentials through patch clamping [2] The specific cell - based experiments are not described in detail in the reference. However, it can be inferred that electrophysiological methods are used to record NMDAR - mediated synaptic responses in inhibitory and excitatory neurons. GNE - 8324 is added to the cell culture environment, and then the synaptic response currents are measured under low - frequency stimulation to observe the effect of GNE - 8324 on NMDAR - mediated synaptic responses in different types of neurons. |
| Animal Protocol |
- Experimental animals: (GAD_{67})-GFP knock-in mice were used to facilitate the identification of inhibitory neurons.
- Drug treatment: M-8324 (a derivative of GNE-8324) was administered via in vivo infusion. - Electrophysiological recording: Whole-cell recording was used to record the spontaneous firing of inhibitory neurons in layers 2/3 of the primary auditory cortex (AI). M-8324 was perfused at a concentration of 30 μM to observe its effect on the firing frequency of neurons. - Sound-evoked experiments: Experiments were conducted using two anesthetics to record the spontaneous firing and sound-evoked firing of neurons in the AI region, aiming to study the effect of M-8324 on the firing of inhibitory neurons under natural input conditions and observe its impact on the balance between excitation and inhibition. - Tinnitus-related experiments: M-8324 was infused before noise exposure to observe whether it could prevent the occurrence of tinnitus and detect its improvement effect on the reduction of GABAergic functions/markers related to tinnitus. |
| References |
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| Additional Infomation |
GNE-8324 is a tool compound used to study the role of NMDAR containing the GluN2A subunit in inhibitory neurons. Its selective modulation of inhibitory neurons makes it a potential candidate for treating brain disorders characterized by excitation/inhibition imbalance, such as epilepsy and autism. Its derivative, M-8324, retains the activity of GNE-8324 and is used in vivo to explore its long-term effects on neural circuits [1] [2]
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| Molecular Formula |
C18H18FN3OS
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|---|---|
| Molecular Weight |
343.418426036835
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| Exact Mass |
343.115
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| Elemental Analysis |
C, 62.95; H, 5.28; F, 5.53; N, 12.24; O, 4.66; S, 9.34
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| CAS # |
1698901-76-6
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| Related CAS # |
:2378608-10-5
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| PubChem CID |
118017713
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| Appearance |
White to off-white solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
634
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C2=NC(=CC(N2C2=C1CCC2)=O)CN(C1C=CC(=CC=1)F)CC
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| InChi Key |
MKBFOAQLSFHEGN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H18FN3OS/c1-2-21(14-8-6-12(19)7-9-14)11-13-10-17(23)22-15-4-3-5-16(15)24-18(22)20-13/h6-10H,2-5,11H2,1H3
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| Chemical Name |
2-((ethyl(4-fluorophenyl)amino)methyl)-7,8-dihydro-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidin-4-one
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| Synonyms |
GNE-8324; GNE 8324; GNE-8,324; 1698901-76-6; 6-[[ethyl-(4-Fluorophenyl)amino]methyl]-2,3-Dihydro-1~{h}-Cyclopenta[3,4][1,3]thiazolo[1,4-~{a}]pyrimidin-8-One; CHEMBL4583809; 10-[(N-ethyl-4-fluoroanilino)methyl]-7-thia-1,9-diazatricyclo[6.4.0.02,6]dodeca-2(6),8,10-trien-12-one; 2-((ethyl(4-fluorophenyl)amino)methyl)-7,8-dihydro-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidin-4-one; orb1697070; SCHEMBL16645583; GNE8324.
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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 (~291.2 mM; with ultrasonication and warming by heating to 60°C)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (14.56 mM) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication and warming and heat to 60°C.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (50.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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: 5 mg/mL (14.56 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication and warming and heat to 60°C. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (50.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 5 mg/mL (14.56 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 DMSO stock solution (50.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9119 mL | 14.5594 mL | 29.1189 mL | |
| 5 mM | 0.5824 mL | 2.9119 mL | 5.8238 mL | |
| 10 mM | 0.2912 mL | 1.4559 mL | 2.9119 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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