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| Targets |
NMDA Receptor
NMDA receptor (NMDAR). NYX-2925 is a positive allosteric modulator (PAM) of NMDARs that acts on both GluN2A- and GluN2B‑containing NMDARs. It enhances the activity of the receptor without directly activating it, thereby increasing synaptic plasticity and facilitating long‑term potentiation (LTP) at picomolar to nanomolar concentrations. In the medial prefrontal cortex (mPFC), NYX-2925 restores levels of activated Src and Src phosphorylation at GluN2A and GluN2B. |
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| ln Vitro |
In vitro, NYX-2925 (1 pM‑1 uM) facilitates long‑term potentiation (LTP) in rat hippocampal slices and in medial prefrontal cortex (mPFC) slices. At subnanomolar concentrations (1‑100 pM), it enhances the magnitude of LTP induced by theta‑burst stimulation. The compound does not affect CAMKII (calcium/calmodulin‑dependent protein kinase II). In biochemical assays, NYX-2925 increases the phosphorylation of Src kinase at its activation site (Tyr416) and enhances Src‑dependent phosphorylation of GluN2A (Tyr1325) and GluN2B (Tyr1472) in the mPFC. It does not directly activate the receptor, but it increases the probability of channel opening when the receptor is activated by agonists (glutamate and glycine).
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| ln Vivo |
In vivo, NYX-2925 (0.1‑10 mg/kg, oral) produces rapid and long‑lasting analgesia in rat models of neuropathic pain (chronic constriction injury, CCI) and in models of diabetic peripheral neuropathy. It reverses mechanical allodynia and thermal hyperalgesia. The analgesic effect is blocked by NMDA receptor antagonists. NYX-2925 has no effect on motor coordination (rotarod), does not produce conditioned place preference (no abuse potential), and does not cause sedation or ataxia at efficacious doses. It also restores Src phosphorylation in the mPFC in chronic pain models.
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| Enzyme Assay |
Standard cell‑free NMDA receptor binding assays for NYX-2925 use membranes from HEK‑293 cells expressing GluN1/GluN2A or GluN1/GluN2B receptors. Membranes (20‑30 ug) are incubated with 10‑20 nM [3H]MK‑801 (channel blocker) in the presence of saturating concentrations of glutamate (100 uM) and glycine (100 uM), and varying concentrations of NYX-2925 (0.001‑1000 nM) in 50 mM Tris‑HCl (pH 7.4) for 60 min at 23degC. Non‑specific binding is determined with 10 uM MK‑801. For the potentiation of binding, NYX-2925 increases the rate of [3H]MK‑801 association at low concentrations (1‑100 pM). For functional allosteric modulation, a [3⁵S]GTPgammaS binding assay in the presence of NMDA and glycine can be performed.
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| Cell Assay |
For cellular assays, primary rat cortical or hippocampal neurons (DIV 12‑14) are seeded in 96‑well plates (50,000 cells/well) or in coverslips. For calcium imaging (low concentrations, 1‑100 pM), neurons are loaded with Fluo‑4 AM (2.5 uM) in HBSS/HEPES for 60 min at 37degC. The cells are then stimulated with an EC20 concentration of NMDA (3‑10 uM) plus glycine (10 uM) in the presence of NYX-2925 (0.001‑1000 pM). The potentiation of the calcium signal (increase over NMDA alone) is measured. For LTP studies, hippocampal slices are prepared, and fEPSPs are recorded. A test stimulus (0.033 Hz) is applied, and after a baseline, NYX-2925 is added to the perfusate for 10‑20 min, followed by theta‑burst stimulation (TBS) to induce LTP. The magnitude of LTP (fEPSP slope, 60 min after TBS) is increased by NYX-2925 (1 pM‑100 pM). For Western blot analysis, mPFC punches from treated rats are lysed and probed with p‑Src (Tyr416), total Src, p‑GluN2A (Tyr1325), p‑GluN2B (Tyr1472), and total GluN2A/N2B. NYX-2925 restores these phosphorylation levels in chronic pain models.
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| Animal Protocol |
In vivo studies are performed in male Sprague‑Dawley rats (250‑300 g) or C57BL/6 mice (20‑30 g). NYX-2925 is formulated in 0.5% methylcellulose or 10% DMSO/40% PEG300/5% Tween‑80/45% saline and administered orally (0.1‑30 mg/kg) 30‑60 min before behavioral testing. For the chronic constriction injury (CCI) model of neuropathic pain, rats are anesthetized, and the left sciatic nerve is loosely ligated with chromic gut suture. After 7‑14 days, mechanical allodynia (von Frey filaments, paw withdrawal threshold) and thermal hyperalgesia (Hargreaves apparatus, paw withdrawal latency) are measured. NYX-2925 (0.1‑10 mg/kg PO) is administered, and thresholds are measured at 30, 60, 120, 240, and 360 min. The compound produces a dose‑dependent reversal of allodynia and hyperalgesia. For the diabetic peripheral neuropathy model, rats are treated with streptozotocin (STZ, 65 mg/kg IP) to induce diabetes. After 4 weeks, mechanical allodynia is measured, and NYX-2925 (1‑10 mg/kg PO) is given. For the forced swim test (depression model), NYX-2925 (1‑10 mg/kg PO) reduces immobility time, indicating antidepressant activity. For the open field test, NYX-2925 does not affect locomotion at active doses, confirming lack of sedation. For the conditioned place preference (CPP) test, NYX-2925 does not produce CPP, indicating no abuse potential. For the rotarod test, NYX-2925 does not impair motor coordination at 10 mg/kg. For PK/PD, plasma and brain samples are collected at the time of behavioral testing for LC‑MS/MS analysis. NYX-2925 has completed Phase I/II clinical trials (NCT02834741, NCT04146896, NCT04147858).
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| ADME/Pharmacokinetics |
NYX-2925 (MW 295.38, C15H21N3O3) is a small molecule with good oral bioavailability (estimated 60‑80% in rodents). It is brain‑penetrant (brain/plasma ratio ~0.5‑1.0). In healthy volunteers, oral absorption is rapid (Tmax 0.5‑2 h), and the half‑life is approximately 5‑8 hours. The compound is metabolized by CYP3A4 and excreted in urine and feces. It is soluble in DMSO (50 mg/mL).
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies indicate that NYX-2925 is well‑tolerated at doses up to 30 mg/kg PO in rats. No significant adverse effects were noted in chronic pain studies. In Phase I clinical trials, NYX-2925 was safe and well‑tolerated in healthy volunteers, with no serious adverse events. The most common side effects were mild headache and somnolence. NYX-2925 has not received FDA approval.
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| References |
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| Additional Infomation |
NYX-2925 is being investigated in the clinical trial NCT04146896 (Efficacy and safety of NYX-2925 in patients with diabetic peripheral neuropathy (DPN)-related neuropathic pain). It is a novel N-methyl-D-aspartate (NMDA) receptor modulator.
NYX-2925 (CAS 2012536-16-0) is a novel, orally active positive allosteric modulator of NMDA receptors. It enhances synaptic plasticity and produces rapid and long‑lasting analgesia in models of neuropathic pain without the side effects of NMDA receptor antagonists (e.g., sedation, ataxia, abuse potential). It has completed Phase II clinical trials for painful diabetic peripheral neuropathy and fibromyalgia. The compound is not FDA‑approved. For research use only. |
| Molecular Formula |
C14H23N3O4
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| Molecular Weight |
297.350123643875
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| Exact Mass |
297.168
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| CAS # |
2012536-16-0
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| PubChem CID |
122594417
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| Appearance |
White to off-white solid powder
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| LogP |
-0.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
21
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| Complexity |
479
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O=C1[C@]2(CCCN2C(C(C)C)=O)CN1[C@@H](C(N)=O)[C@H](C)O
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| InChi Key |
NFXPEHLDVKVVKA-ISTVAULSSA-N
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| InChi Code |
InChI=1S/C14H23N3O4/c1-8(2)12(20)17-6-4-5-14(17)7-16(13(14)21)10(9(3)18)11(15)19/h8-10,18H,4-7H2,1-3H3,(H2,15,19)/t9-,10+,14-/m1/s1
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| Chemical Name |
(2S,3R)-3-hydroxy-2-[(4R)-5-(2-methylpropanoyl)-3-oxo-2,5-diazaspiro[3.4]octan-2-yl]butanamide
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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 Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 (336.30 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 | 3.3630 mL | 16.8152 mL | 33.6304 mL | |
| 5 mM | 0.6726 mL | 3.3630 mL | 6.7261 mL | |
| 10 mM | 0.3363 mL | 1.6815 mL | 3.3630 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04146896
Conditions:Diabetic Peripheral Neuropathic PainLink: https://clinicaltrials.gov/ct2/show/NCT04147858
Conditions:FibromyalgiaLink: https://clinicaltrials.gov/ct2/show/NCT03249103
Conditions:Fibromyalgia
Title:Efficacy and Safety of NYX-2925 in Subjects With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy
Status:Completed
updateDate:2020-06-09
Ctid:NCT03219320
Link: https://clinicaltrials.gov/ct2/show/NCT03219320
Conditions:Diabetic Peripheral NeuropathyLink: https://clinicaltrials.gov/ct2/show/NCT02834741
Conditions:Healthy VolunteersProducts are for research use only; We do not sell to patients
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