Noopept
Noopept is a synthetic dipeptide nootropic compound (cycloprolylglycine analogue) with the chemical structure N-phenylacetyl-L-prolylglycine ethyl ester. It acts as a modulator of AMPA receptor-mediated glutamatergic transmission and an inducer of BDNF/TrkB signaling. In research settings, it is investigated for cognitive enhancement, neuroprotection, memory consolidation, and age-related cognitive decline.
Chemical Profile
| Property |
Value |
| CAS Number |
157115-85-0 |
| IUPAC Name |
Ethyl 2-[(2S)-1-(2-phenylacetyl)pyrrolidine-2-amido]acetate |
| Chemical Formula |
C₁₇H₂₂N₂O₄ |
| Molecular Weight |
342.39 g/mol |
| SMILES |
CCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)Cc1ccccc1 |
| Purity (HPLC) |
≥ 99% |
Noopept at a Glance
- Class: Dipeptide nootropic (cycloprolylglycine analogue)
- Research Status: Preclinical and clinical (Russia)
- Route: Oral, sublingual
- Half-life: ~2–5 hours (oral)
- CAS: 157115-85-0
- MW: 342.4 Da
- Key Feature: AMPA receptor facilitation; BDNF induction
Mechanism of Action
Noopept was designed as a non-peptide mimetic of the endogenous cyclic dipeptide cyclo-L-prolylglycine (CPG), a metabolite of the nootropic drug piracetam. It exhibits a multimodal mechanism of action.
Primary Signaling Pathways
| Component |
Detail |
| Primary Target |
AMPA-type glutamate receptors (positive allosteric modulation) |
| BDNF/TrkB |
Upregulates BDNF expression; activates TrkB receptors |
| Secondary Targets |
NMDA receptors (modulation), nAChRs (enhancement) |
| Calcium Signaling |
Moderate Ca²⁺ influx via AMPA receptors |
| CREB Pathway |
CREB phosphorylation → memory-related gene expression |
| Antioxidant |
Reduces lipid peroxidation in brain homogenates |
| Cholinergic |
Enhances acetylcholine release in hippocampus |
Comparison with Piracetam
| Property |
Noopept |
Piracetam |
| Chemical Class |
Dipeptide analogue |
Cyclic GABA derivative |
| Potency |
~1000× more potent than piracetam |
1× reference |
| Oral Dose |
10–30 mg/day |
1.6–4.8 g/day |
| BDNF Induction |
Yes (direct) |
Indirect |
| AMPA Modulation |
Yes |
Weak |
| Half-life |
2–5 hours |
4–6 hours |
Pharmacodynamic Effects
| System |
Effect |
Mechanism |
| Hippocampus |
Enhanced LTP |
AMPA facilitation → Ca²⁺ → ERK/CREB |
| Cortex |
Increased neuronal metabolic activity |
Mitochondrial enhancement |
| Memory Consolidation |
Improved |
Enhanced neuroplasticity |
| EEG |
Increased α-wave activity |
CNS activation pattern |
Pharmacology
| Parameter |
Value |
| Half-life (t½) |
~2–5 hours (oral) |
| Bioavailability (Oral) |
~50–70% |
| Tmax |
~1–2 hours |
| Volume of Distribution (Vd) |
~0.8–1.2 L/kg |
| Protein Binding |
~40% |
| Metabolism |
Hepatic (ester hydrolysis → N-phenylacetyl-L-prolylglycine) |
| Active Metabolite |
N-phenylacetyl-L-prolylglycine (pharmacologically active) |
| Route |
Oral, sublingual |
| Elimination |
Renal (metabolites) |
| BBB Permeability |
High (passive diffusion, ~4% of plasma concentration in brain) |
Research Evidence
Dosing Reference
| Parameter |
Recommendation |
| Research Dose Range |
10–20 mg (oral); 10–15 mg (sublingual) |
| Dosing Frequency |
2–3 times daily |
| Duration |
1–3 months (cycle), with 1–2 week washout |
| Reconstitution |
Soluble in water or saline |
| Storage (Powder) |
2–8°C, desiccated, light-protected |
| Storage (Solution) |
2–8°C for up to 14 days |
Safety Profile
| Category |
Observations |
| Most Common |
Mild digestive disturbance at high doses |
| Neurological |
Headache (rare, dose-dependent); irritability (rare) |
| CNS |
No sedation; mild stimulatory effect in some subjects |
| Contraindications |
For research use only; not for human or veterinary application |
| Drug Interactions |
Potential additive effects with other nootropics |
| Immunogenicity |
Very low (small molecule) |
Physicochemical Properties
| Property |
Value |
| Physical State |
White crystalline powder |
| Solubility (Water) |
~2 mg/mL |
| Solubility (Ethanol) |
Soluble (> 20 mg/mL) |
| Solubility (DMSO) |
Soluble (> 50 mg/mL) |
| logP |
~0.8 (moderately lipophilic) |
| Melting Point |
~120–125°C |
| Stability (Powder) |
≥ 36 months at 2–8°C |
| Stability (Solution) |
14 days at 2–8°C |
Synthetic Chemistry
Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) is a synthetic dipeptide mimetic prepared by classical organic synthesis rather than solid-phase peptide synthesis.
Synthetic Route
| Step |
Reaction |
Condition |
| 1. Acylation |
Phenylacetyl chloride + L-proline → N-phenylacetyl-L-proline |
Schotten-Baumann (aq. NaOH/THF, 0–5°C, 2 h) |
| 2. Activation |
N-phenylacetyl-L-proline + HOBt/DCC → activated ester |
DMF, 0°C to RT, 1 h |
| 3. Coupling |
Activated ester + glycine ethyl ester → Noopept |
DMF, RT, 4 h |
| 4. Workup |
Extract (EtOAc), wash (5% NaHCO₃, brine), dry (Na₂SO₄) |
Standard |
| 5. Purification |
Silica gel column (CHCl₃/MeOH, 95:5) or recrystallization |
Yield: 65–80% |
| 6. Characterization |
¹H/¹³C NMR, MS, HPLC (≥ 99%) |
Identity + purity |
Key Synthetic Considerations
- The ethyl ester group is critical for oral bioavailability; hydrolysis yields the active metabolite (N-phenylacetyl-L-prolylglycine)
- Noopept exists as a single stereoisomer (L-proline configuration at the chiral center)
- The compound is stable to standard silica gel chromatography but sensitive to strong bases (ester hydrolysis)
- Alternative synthetic routes employ carbodiimide coupling (EDC/HOBt) or mixed anhydride methods
Analytical Methods
HPLC
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| Parameter |
Condition |
| Column |
C18 (4.6 × 250 mm, 5 μm) |
| Mobile Phase |
A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile |
| Gradient |
20–60% B over 20 min |
| Flow Rate |
1.0 mL/min |
| Detection |
UV 220 nm |
| Retention Time |
~10–12 min |
LC-MS
| Parameter |
Condition |
| Ionization |
ESI+ |
| Detected (M+H)+ |
~343.4 Da |
| Detection (M+Na)+ |
~365.4 Da |
NMR
| Nucleus |
Key Resonances |
| ¹H NMR (DMSO-d₆) |
Aromatic at δ 7.2–7.4 (5H), ester CH₂ at δ 4.1, CH₃ at δ 1.2 |
Stability Data
| Condition |
Storage Parameters |
Stability |
| Powder (−20°C) |
Desiccated, light-protected, sealed vial |
≥ 36 months |
| Powder (4°C) |
Desiccated, light-protected |
≥ 24 months |
| Powder (25°C) |
Ambient, < 40% RH |
~12 months |
| Solution (2–8°C) |
Aqueous, pH 5–7, sterile |
14 days |
| Solution (25°C) |
Aqueous, pH 5–7 |
~72 h |
| Solution (−20°C) |
Aqueous, single-use aliquots |
~3 months |
| Ethanol Solution |
20 mg/mL in EtOH, 2–8°C |
≥ 6 months |
| Freeze-Thaw Stability |
3 cycles, −20°C to 25°C |
< 2% degradation per cycle |
| Acidic Hydrolysis |
0.1 M HCl, 37°C, 24 h |
~40% ester hydrolysis |
| Basic Hydrolysis |
0.1 M NaOH, 37°C, 1 h |
Complete ester hydrolysis |
Noopept's primary degradation pathway in solution is hydrolysis of the ethyl ester group, yielding the free carboxylic acid metabolite (N-phenylacetyl-L-prolylglycine). The compound is most stable in slightly acidic to neutral pH (5–7). Lyophilized or crystalline powder stored at 4–8°C in the dark provides the longest practical shelf life.
References
- Ostrovskaya RU, et al. (2007). Noopept — a novel nootropic and neuroprotective agent. Neurochemical Research. DOI: 10.1007/s11064-007-9337-2
- Vakhitova YV, et al. (2005). Noopept modulation of AMPA receptors. Neurochemical Research. DOI: 10.1007/s11064-005-1634-z
- Zenina TA, et al. (2007). Noopept reverses scopolamine-induced amnesia. Bulletin of Experimental Biology and Medicine. DOI: 10.1007/s10517-007-0469-1
- Povarnina PY, et al. (2011). Neuroprotective effect of Noopept in focal ischemia. Neurochemical Research. DOI: 10.1007/s11064-011-0458-2
- Bobkova NV, et al. (2003). Noopept effect on memory in aged mice. Neuroscience and Behavioral Physiology. DOI: 10.1023/A:1023936603470
- Andreeva LA, et al. (2000). Design and synthesis of Noopept. Russian Journal of Bioorganic Chemistry.
- Gulyaeva NV, et al. (2006). Noopept antioxidant effects in brain. Neuroscience Research.
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