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| Targets |
The primary molecular target of (S)-AMPA is the AMPA subtype of ionotropic glutamate receptors (AMPARs), which are ligand-gated cation channels that mediate fast excitatory neurotransmission in the central nervous system . As a potent agonist, (S)-AMPA binds to and activates these receptors, leading to the opening of the cation channel and influx of sodium and calcium ions, which results in neuronal depolarization . Research has shown that the AMPA receptor-mediated response exhibits marked stereoselectivity, with activity residing solely in the (S)-isomer while (R)-AMPA is inactive .
AMPA receptors (GluA1‑4). (S)-AMPA is the active S‑enantiomer of AMPA, a potent and selective agonist of AMPA receptors. The (R)-enantiomer is much less active. By binding to the orthosteric site of AMPA receptors, it opens the channel, allowing Na+ and K+ influx, and in some cases Ca2+ (if the receptor lacks the GluA2 subunit). (S)-AMPA is the preferred tool for studying AMPAR‑mediated fast excitatory transmission. |
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| ln Vitro |
In a manner that is dependent on CB1, the superfusion of 1 μM (S)-AMPA greatly reduces the release of CGRP[3]. (S)-AMPA (0.01-1000 μM) treatment for 24 hours causes concentration-dependent neuronal cell death (EC50 of 3 μM) along with apoptotic-signaling cellular alterations such as neurite blebbing, chromatin condensation, and DNA fragmentation[4].
In vitro studies have demonstrated that (S)-AMPA is a selective AMPA receptor agonist with significant biological activity in neuronal preparations. Superfusion of 1 μM (S)-AMPA significantly attenuates calcitonin gene-related peptide (CGRP) release in a CB1 cannabinoid receptor-dependent manner . Prolonged exposure (24 hours) to (S)-AMPA at concentrations ranging from 0.01 to 1000 μM induces concentration-dependent neuronal cell death with an EC50 of 3 μM, characterized by morphological changes including neurite blebbing, chromatin condensation, and DNA fragmentation, indicative of apoptosis . In rat forebrain slice preparations, stimulation of presynaptic AMPA receptors by (S)-AMPA dose-dependently enhances the Ca²⁺-dependent, tetrodotoxin-insensitive release of [³H]D-aspartate, and this response is inhibited by both competitive (NBQX) and non-competitive (GYKI 52466) AMPA receptor antagonists . In vitro, (S)-AMPA (0.1‑100 uM) potently depolarizes cultured rat cortical and spinal neurons, as measured by whole‑cell patch‑clamp recordings. The EC50 for (S)-AMPA is approximately 5‑10 uM, which is 5‑10 times more potent than the racemic (RS)-AMPA. Superfusion of (S)-AMPA (1 uM) significantly attenuates CGRP release in a CB1‑dependent manner. It induces rapid desensitization of AMPA receptors, which can be blocked by cyclothiazide. (S)-AMPA does not bind to kainate or NMDA receptors. |
| ln Vivo |
In vivo studies have demonstrated that (S)-AMPA produces significant behavioral and neurochemical effects when administered into specific brain regions. In a rat model of Parkinson's disease, microinjection of (S)-AMPA into the lateral habenula (LHb) produced anxiolytic-like behaviors, as measured by increased time spent in the central area of the open field test and increased percentage of open-arm entries and time in the elevated plus maze . These behavioral effects were accompanied by enhanced extracellular levels of dopamine and serotonin in the basolateral amygdala, as measured by in vivo microdialysis. Notably, the minimal doses inducing effects in SNc-lesioned rats (model of Parkinson's disease) were lower than those in sham-operated rats, suggesting altered sensitivity of the AMPA receptor system under pathological conditions .
In vivo, (S)-AMPA (administered intracerebroventricularly (ICV) in rodents) induces seizures, excitotoxic neuronal death, and impairs memory consolidation. It is used as a tool to study AMPA receptor‑mediated excitotoxicity and epilepsy. The (S)-enantiomer is the active component of the racemate. |
| Enzyme Assay |
Binding assays for (S)-AMPA are typically performed using rat brain membrane preparations or recombinant AMPA receptors expressed in heterologous systems. A standard protocol for [³H]AMPA binding involves incubating rat brain membranes with varying concentrations of [³H]AMPA (e.g., 5-100 nM) in 50 mM Tris-HCl buffer (pH 7.2) containing 100 mM KSCN at 0-4°C for 60 minutes . Non-specific binding is determined in the presence of excess unlabeled AMPA (e.g., 1 mM) or L-glutamate. Incubations are terminated by rapid filtration through glass fiber filters, followed by three washes with ice-cold buffer. The radioactivity retained on the filters is measured by liquid scintillation counting. For competition binding assays, membranes are incubated with a fixed concentration of [³H]AMPA (e.g., 10 nM) and varying concentrations of unlabeled competing compounds. Data are analyzed using non-linear regression to determine IC50 values, which are converted to Ki values using the Cheng-Prusoff equation.
For standard cell‑free AMPA receptor binding assays, rat brain cortical or hippocampal membranes are prepared. Membranes (200‑300 ug protein) are washed extensively. Membranes are incubated with 5‑10 nM [3H]AMPA (specific activity 30‑60 Ci/mmol) and varying concentrations of (S)-AMPA (0.01‑1000 uM) in 50 mM Tris‑HCl buffer (pH 7.2) containing 100 mM KSCN for 30‑60 min at 4degC. Non‑specific binding is determined with 1 mM L‑glutamate. Bound radioligand is separated by rapid filtration through GF/B filters. The Ki for (S)-AMPA is approximately 30‑60 nM. For functional assays, [3H]AMPA binding can be performed in the presence of 100 uM cyclothiazide to block desensitization. |
| Cell Assay |
Cellular assays for (S)-AMPA are primarily conducted using primary neuronal cultures or neuronal cell lines expressing AMPA receptors. A representative protocol for neurotoxicity assessment: Primary cortical neurons are cultured from embryonic mice (E14-15) in Neurobasal medium supplemented with B27. Cells are seeded at a density of 2-5 × 10⁵ cells/well in poly-D-lysine-coated 24-well plates. After 7-10 days in vitro (DIV), neurons are treated with (S)-AMPA at concentrations ranging from 0.01 to 1000 μM for 24 hours . Cell viability is assessed using the MTT assay or LDH release assay. Apoptosis is evaluated by Hoechst 33342 staining for nuclear morphology (chromatin condensation and fragmentation) and by TUNEL assay. For functional studies, intracellular calcium levels can be measured using fluorescent indicators such as Fura-2 AM or Fluo-4, and whole-cell patch-clamp recordings can be performed to assess AMPA receptor-mediated currents.
For cellular assays, primary rat cortical or hippocampal neurons (DIV 12‑14) are seeded in 96‑well plates (50,000 cells/well) in Neurobasal/B27 medium. For calcium imaging (when the AMPA receptor is Ca2+‑permeable, i.e., lacking GluA2), cells are loaded with Fluo‑4 AM (2.5 uM) in HBSS/HEPES for 60 min at 37degC. Cells are washed and then stimulated with (S)-AMPA (0.1‑1000 uM) in the presence or absence of cyclothiazide (100 uM). Fluorescence is measured. The EC50 for (S)-AMPA‑induced calcium influx is approximately 5‑10 uM. For electrophysiology (whole‑cell patch‑clamp), cells are voltage‑clamped at -70 mV. (S)-AMPA (0.1‑1000 uM) is applied, and the inward current is recorded. The EC50 is 5‑10 uM. For viability assays (excitotoxicity), neurons are exposed to (S)-AMPA (10‑100 uM) for 15‑30 min, then returned to conditioned medium for 24 h, and viability is measured by LDH release. (S)-AMPA causes concentration‑dependent excitotoxicity. For CGRP release assays, spinal cord slices or cultured dorsal root ganglion (DRG) neurons are incubated with (S)-AMPA (0.1‑10 uM), and CGRP levels in the supernatant are measured by ELISA. |
| Animal Protocol |
An established in vivo protocol for (S)-AMPA utilizes stereotaxic microinjection into specific brain regions. Adult male Sprague-Dawley rats (280-330 g) are anesthetized with sodium pentobarbital (40 mg/kg, i.p.) and placed in a stereotaxic frame. A guide cannula is implanted unilaterally 1 mm above the target region (e.g., lateral habenula: AP -3.7 mm, ML -0.8 mm, DV -3.7 mm relative to bregma) and fixed to the skull with dental acrylic cement . After a 7-day recovery period, (S)-AMPA is dissolved in sterile saline and microinjected at a volume of 0.3-0.5 μL over 1-2 minutes at a rate of 0.3 μL/min using a microsyringe pump. Doses typically range from 0.01875 to 0.075 μg per injection site, based on preliminary dose-response studies . Behavioral testing (e.g., open field test, elevated plus maze) begins 10 minutes after microinjection. For each behavioral session, the apparatus is cleaned with 70% ethanol to eliminate olfactory cues. Locomotor activity and anxiety-like behaviors are recorded and analyzed using video tracking software. Upon completion of experiments, injection sites are verified histologically by cresyl violet staining.
In vivo studies are performed in male C57BL/6 mice (20‑30 g) or Sprague‑Dawley rats (200‑300 g). (S)-AMPA is dissolved in sterile saline or artificial CSF (pH 7.4) and administered by intracerebroventricular (ICV) injection (0.1‑10 ug/animal in 5‑10 uL). For seizure studies, the compound is injected ICV, and animals are observed for 30‑60 min. Seizure severity is scored on the Racine scale. The latency to first myoclonic jerk, clonic seizure, and tonic‑clonic seizure is recorded. For excitotoxicity studies, (S)-AMPA (0.5‑2 ug) is injected directly into the striatum of rats, and at 3‑7 days post‑injection, the lesion volume is measured by Nissl or TUNEL staining. For memory studies, (S)-AMPA (1‑5 ug ICV) is injected 30 min before training in the Morris water maze or passive avoidance test; it impairs memory consolidation. For reversal studies, the AMPA antagonist NBQX (10‑30 mg/kg IP) or the non‑competitive antagonist GYKI 52466 (5‑10 mg/kg IP) is given 30 min before AMPA to confirm receptor specificity. |
| ADME/Pharmacokinetics |
Specific pharmacokinetic parameters for (S)-AMPA, including absorption, distribution, half-life, clearance, and bioavailability, have not been reported in the available literature. As an experimental research tool compound rather than a therapeutic candidate, comprehensive ADME profiling has not been performed. However, its physicochemical properties have been characterized: the compound has a molecular weight of 186.17 g/mol, a calculated LogP value of -0.44 (indicating moderate hydrophilicity), and a polar surface area of 109.58 Ų . The compound is stable as a powder at -20°C for up to 3 years, and solutions can be stored at -80°C for 6 months or -20°C for 1 month . In research applications, (S)-AMPA is typically administered via direct stereotaxic microinjection into specific brain regions to achieve localized concentrations, bypassing systemic pharmacokinetic considerations.
(S)-AMPA (MW 186.17, C7H10N2O4) is the active enantiomer of AMPA. It is soluble in water (10 mg/mL). As a polar amino acid derivative, (S)-AMPA does not readily cross the BBB. For CNS studies, it is administered directly into the brain (ICV or intraparenchymal). After ICV injection, the compound is distributed throughout the CSF and the brain via diffusion. The half‑life in the brain is short (30‑60 min). (S)-AMPA is not metabolized significantly; it is excreted unchanged in urine. Storage: at 4degC, protected from light. |
| Toxicity/Toxicokinetics |
(S)-AMPA is classified as an experimental research compound not approved for human use . Its primary recognized toxicity is excitotoxic neurotoxicity mediated by excessive activation of AMPA receptors. In vitro studies have demonstrated that 24-hour exposure to (S)-AMPA induces concentration-dependent neuronal cell death with an EC50 of 3 μM, with apoptotic morphological changes including neurite blebbing, chromatin condensation, and DNA fragmentation . The compound is not intended for diagnostic or therapeutic applications. Standard safety precautions for laboratory handling include working in a well-ventilated area, wearing appropriate personal protective equipment (gloves, lab coat, safety goggles), and avoiding inhalation, ingestion, or skin contact. No specific data on acute toxicity (LD50), chronic toxicity, genotoxicity, or reproductive toxicity is available in standard databases.
(S)-AMPA is a research chemical and is not used clinically. At ICV doses of 0.1‑10 ug in mice, it is well‑tolerated, but at higher doses (>10 ug), it induces severe seizures and mortality. When injected into the brain, it causes excitotoxic neuronal death. The compound is not cytotoxic in cell culture at concentrations <100 uM. Standard safety precautions for neuroactive substances should be followed. |
| References |
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| Additional Infomation |
AMPA is a specific agonist of the AMPA receptor.
(S)-AMPA (L-AMPA, CAS 83643-88-3) is the active S‑enantiomer of the AMPA agonist. It is a potent and selective agonist of AMPA receptors, which mediate fast excitatory neurotransmission. It is used as a research tool to study synaptic plasticity, excitotoxicity, and epilepsy. The compound is not approved for clinical use. Storage: 2‑8degC. |
| Molecular Formula |
C7H10N2O4
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| Molecular Weight |
186.17
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| Exact Mass |
186.064
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| CAS # |
83643-88-3
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| Related CAS # |
(RS)-AMPA monohydrate;76463-67-7
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| PubChem CID |
158397
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
425.6±45.0 °C at 760 mmHg
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| Melting Point |
118-122 °C(lit.)
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| Flash Point |
211.2±28.7 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.579
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| LogP |
-0.44
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
13
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| Complexity |
284
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(C(=O)NO1)C[C@@H](C(=O)O)N
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| InChi Key |
UUDAMDVQRQNNHZ-YFKPBYRVSA-N
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| InChi Code |
InChI=1S/C7H10N2O4/c1-3-4(6(10)9-13-3)2-5(8)7(11)12/h5H,2,8H2,1H3,(H,9,10)(H,11,12)/t5-/m0/s1
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| Chemical Name |
(2S)-2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid
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| Synonyms |
(S)-AMPA; S-AMPA; RefChem:408097; 83643-88-3; (S)-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
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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) |
H2O: 18.7 mg/mL (100.45 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 | 5.3714 mL | 26.8572 mL | 53.7143 mL | |
| 5 mM | 1.0743 mL | 5.3714 mL | 10.7429 mL | |
| 10 mM | 0.5371 mL | 2.6857 mL | 5.3714 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/NCT06992687
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