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| Targets |
The primary target of E1R is the sigma-1 receptor (Sig1R). The sigma-1 receptor is a unique protein that acts as a ligand-regulated chaperone. It is highly expressed in the brain, particularly in regions involved in cognition and emotion, such as the hippocampus and the prefrontal cortex. The receptor is involved in modulating the activity of various ion channels and neurotransmitter receptors, including NMDA and dopamine receptors. It plays a crucial role in neuroprotection, neuroplasticity, and the regulation of intracellular calcium homeostasis. By positively modulating the sigma-1 receptor, E1R enhances its activity, leading to downstream effects that promote neuronal health and cognitive function. Its positive allosteric modulation means it enhances the receptor's response to endogenous ligands, which is often a more physiological and safer approach than direct agonism.
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| ln Vitro |
Sigma receptors are the sole receptors that E1R targets and that either increases or decreases radioligand binding by more than 20%. The non-selective radioligand ([3H]1,3-bis(2-tolyl)guanidine) is more specifically bound to sigma receptors in Jurkat cells by 38% at 10 μM E1R, although it does not displace the radioligand [1].
E1R is a selective and potent positive allosteric modulator of the sigma-1 receptor. As a PAM, its activity is dependent on the presence of the endogenous ligand. In vitro, its activity is typically characterized using receptor binding and functional assays. In receptor binding assays, it can be shown to bind to the sigma-1 receptor in a manner distinct from the orthosteric site. In functional assays, such as calcium mobilization assays, E1R enhances the response of the receptor to a sub-maximal concentration of a known sigma-1 agonist. Its cognition-enhancing activity has been demonstrated in vitro through its ability to modulate neurotransmitter release and promote neuronal survival. |
| ln Vivo |
E1R is effective in preventing mice's cholinergic dysfunction brought on by scopolamine. Mice's cognitive performance was markedly improved in a dose-related manner by E1R therapy (0.1–10 mg/kg; intraperitoneally administered 60 minutes before to training) [1].
E1R has demonstrated in vivo activity in animal models. It has been shown to be effective against scopolamine-induced cholinergic dysfunction in mice. In this model, scopolamine, a muscarinic acetylcholine receptor antagonist, is used to induce cognitive deficits. Treatment with E1R was able to reverse these deficits, improving cognitive performance. This demonstrates the compound's potential as a cognition-enhancing agent. These in vivo studies are crucial for translating the in vitro findings into a functional behavioral effect. |
| Enzyme Assay |
The in vitro receptor binding assay for E1R typically involves measuring its affinity for the sigma-1 receptor using radioligand binding. Membranes prepared from cells or tissues expressing the sigma-1 receptor are incubated with a radiolabeled ligand specific for the sigma-1 receptor (e.g., ³H-pentazocine or ³H-(+)-SKF-10047) in the presence of varying concentrations of E1R. The amount of radioligand bound to the receptor is measured. A reduction in radioligand binding in the presence of E1R indicates that it is binding to the receptor. However, as a PAM, its mode of binding is allosteric, so it may not completely displace the orthosteric ligand. Functional assays are more informative for PAMs.
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| Cell Assay |
In vitro cell-based assays for E1R evaluate its functional activity as a PAM. One common assay is the measurement of intracellular calcium levels. Cells expressing the sigma-1 receptor are loaded with a calcium-sensitive fluorescent dye. The cells are then treated with a sub-maximal concentration of a sigma-1 agonist, such as pregnenolone sulfate or dehydroepiandrosterone (DHEA), to elicit a calcium response. The addition of E1R should potentiate this calcium response, confirming its PAM activity. This is a robust and widely used method for characterizing PAMs.
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| Animal Protocol |
Animal/Disease Models: Male ICR and balb/c (Bagg ALBino) mouse, body weight 23-25 g[1]
Doses: 0.1, 1 and 10 mg/kg Route of Administration: intraperitoneal (ip) injection 60 minutes before training Experimental Results: at 1 and 10 mg/kg Compared with the control group, retention latency increased by 194% and 211% respectively. In vivo animal studies for E1R have focused on its cognition-enhancing properties. A common model is the scopolamine-induced amnesia model in mice or rats. In this model, animals are treated with scopolamine to induce memory deficits. They are then treated with E1R, and their cognitive performance is assessed using behavioral tests such as the Morris water maze, the Y-maze, or the novel object recognition test. E1R has been shown to improve cognitive performance in these tests. These studies are essential for demonstrating its therapeutic potential. |
| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for E1R is not provided in the search results. Its molecular weight is 232.28. As a small molecule, it is likely to have good oral bioavailability and blood-brain barrier penetration, which is consistent with its central activity.
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| Toxicity/Toxicokinetics |
Specific toxicity data for E1R is not publicly available. As a PAM, it is expected to have a more favorable safety profile than an agonist, as its effects are dependent on the presence of the endogenous ligand. It is classified as a research tool and is not intended for human use.
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| References | |
| Additional Infomation |
E1R is a research compound being developed as a positive allosteric modulator of the sigma-1 receptor for the treatment of cognitive disorders. Its novel mechanism of action and cognition-enhancing properties make it a promising candidate for further development. The compound has not received FDA approval.
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| Molecular Formula |
C13H16N2O2
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| Molecular Weight |
232.28
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| Exact Mass |
232.121
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| CAS # |
1301211-78-8
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| Related CAS # |
(2R,3S)-E1R;1424832-60-9;(2S,3S)-E1R;1424832-57-4;(2R,3R)-E1R;1400888-63-2;(Rac)-E1R;787623-60-3
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| PubChem CID |
52912210
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
0.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
17
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| Complexity |
311
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O=C1C[C@H](C2C=CC=CC=2)[C@H](C)N1CC(N)=O
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| InChi Key |
ZTGRWYMPQCQTHD-ONGXEEELSA-N
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| InChi Code |
InChI=1S/C13H16N2O2/c1-9-11(10-5-3-2-4-6-10)7-13(17)15(9)8-12(14)16/h2-6,9,11H,7-8H2,1H3,(H2,14,16)/t9-,11-/m0/s1
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| Chemical Name |
2-[(2S,3R)-2-methyl-5-oxo-3-phenylpyrrolidin-1-yl]acetamide
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| Synonyms |
E 1 R; E-1-R; E1R
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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 : ~60 mg/mL (~258.31 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 | 4.3051 mL | 21.5257 mL | 43.0515 mL | |
| 5 mM | 0.8610 mL | 4.3051 mL | 8.6103 mL | |
| 10 mM | 0.4305 mL | 2.1526 mL | 4.3051 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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