Description
Summary Abstract
Noopept (GVS-111; N-phenylacetyl-L-prolylglycine ethyl ester; Ethyl 1-(phenylacetyl)-L-prolylglycinate; C17H22N2O4; MW 318.37 g/mol; CAS 157115-85-0) is a synthetic dipeptide nootropic agent developed at the Zakusov State Research Institute of Pharmacology in Russia in 1996 as a structurally novel analogue of piracetam with approximately 1000-fold greater potency. Noopept is a prodrug that is rapidly metabolized after oral administration to the endogenous neuropeptide cycloprolylglycine (cPG), which is responsible for the majority of its biological activity. cPG functions as a positive allosteric modulator of AMPA receptors, enhancing glutamatergic transmission and facilitating the AMPA-mediated depolarization required for NMDA receptor activation and long-term potentiation (LTP) — the cellular substrate of memory consolidation. Chronic administration upregulates hippocampal BDNF and NGF mRNA and protein expression. Noopept also sensitizes α7 nicotinic acetylcholine receptors on hippocampal interneurons, increasing GABAergic inhibitory tone and producing anxiolytic effects. Broad-spectrum neuroprotection includes anti-excitotoxic, antioxidant, anti-inflammatory (IL-6 ↓, IL-4 ↑), and anti-apoptotic properties active against amyloid-β toxicity and α-synuclein aggregation. An open-label Russian comparative trial (n=41 completers) found Noopept at 20 mg/day superior or comparable to piracetam at 1200 mg/day for MCI of vascular and traumatic origin, with 1.8× fewer adverse events. Noopept is approved and available OTC in Russia; it is an unapproved New Drug in the United States.
Clinical Indications
Noopept’s “Glutamate-to-Growth” signaling cascade supports investigation across cognitive and neuroprotective domains:
- Mild Cognitive Impairment (MCI) — Vascular and Post-Traumatic: Open-label comparative trial (Neznamov & Teleshova, 2009): 20 mg/day Noopept demonstrated more pronounced cognitive restoration than 1200 mg/day piracetam in TBI-related MCI and normalized autonomic nervous system function (headache, dizziness, sleep).
- Alzheimer’s Disease (Preclinical): Protected PC12 cells from Aβ-induced toxicity; reduced tau hyperphosphorylation at Ser396; preserved neurite outgrowth morphology; activated BDNF/TrkB and anti-apoptotic Akt pathways.
- Parkinson’s Disease (Preclinical): Modulated α-synuclein amyloid assembly toward less cytotoxic fibrillar aggregates; reversed motor symptoms and dopaminergic neuron loss in PINK1-knockout rats with intranasal Noopept + Forskolin.
- Anxiety Disorders: Genotype-dependent anxiolytic activity via α7-nAChR-mediated hippocampal GABAergic interneuron stimulation; independently confirmed for the cPG metabolite in rodent models.
- Post-Stroke Cognitive Rehabilitation: A separate open-label Russian study (n=60 stroke patients) reported significant cognitive improvement at 20 mg/day over two months.
Contraindications
- Personal or Family History of Psychosis or Bipolar Disorder: AMPA receptor potentiation carries a biologically plausible risk of psychiatric destabilization in individuals with vulnerable glutamatergic systems; piracetam-class compounds have case-report associations with psychosis.
- Hypertension (Monitor): Blood pressure elevation was reported in 7 of 31 patients in the primary clinical trial; cardiovascular monitoring is appropriate.
- Pregnancy: No gestational safety data; glutamatergic modulation during fetal development is contraindicated.
- Concurrent Glutamatergic or Dopaminergic Agents: AMPA potentiation and potential dopamine-transporter inhibition create theoretical pharmacodynamic interaction risks.
Mechanism of Action (MOA)
Noopept’s pharmacology operates through a “Glutamate-to-Growth” cascade that links immediate synaptic enhancement to long-term neurorestorative structural changes:
cPG: Positive AMPA Receptor Modulation
The active metabolite cycloprolylglycine (cPG) functions as an endogenous ampakine, binding allosterically to AMPA receptors (particularly GluA3 subtype) and enhancing their response to glutamate. Electrophysiological studies in rat cerebellar Purkinje cells confirm significantly enhanced AMPA-mediated transmembrane currents. This augmented AMPA depolarization provides the threshold voltage needed to relieve the Mg²⁺ block of NMDA receptors, enabling Ca²⁺ influx and initiating LTP — the cellular basis of memory formation.
BDNF and NGF Upregulation
Chronic Noopept administration (28 days) significantly increases hippocampal BDNF and NGF mRNA and protein levels. cPG independently drives BDNF upregulation; neuroprotective effects of cPG are abolished by TrkB receptor antagonists, confirming BDNF/TrkB as the downstream mediator of cellular survival. This creates a two-stage mechanism: acute AMPA potentiation triggers glutamate-dependent BDNF synthesis, which then drives structural synaptic remodeling, neurogenesis, and long-term neuronal survival.
α7 nAChR Modulation → Anxiolysis
Electrophysiological recordings in rat hippocampal CA1 slices show that Noopept increases inhibitory postsynaptic current (IPSC) frequency in pyramidal neurons via activation of α7 nicotinic acetylcholine receptors on GABAergic interneurons. This enhanced GABAergic inhibitory tone produces anxiolytic effects independent of benzodiazepine binding sites. The effect is blocked by α-bungarotoxin and methyllycaconitine (α7-nAChR antagonists), confirming mechanistic specificity.
Multi-Modal Neuroprotection
Noopept and cPG provide broad-spectrum neuronal protection: anti-excitotoxic (prevents glutamate-Ca²⁺ overload); antioxidant (reduces intracellular ROS); anti-inflammatory (↓IL-6, ↑IL-4 in amyloid-β infusion models); anti-apoptotic (enhances mitochondrial membrane potential, suppresses caspase pathways); and tau-modifying (↓Tau hyperphosphorylation at Ser396 and preservation of neurite outgrowth).
Key Features & Specifications
Noopept combines a well-characterized mechanism, Russian regulatory approval, and superior tolerability vs. piracetam:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| IUPAC Name | Ethyl 1-(phenylacetyl)-L-prolylglycinate |
| CAS Number | 157115-85-0 |
| Molecular Formula | C17H22N2O4 |
| Molecular Weight | 318.37 g/mol |
| PubChem CID | 180496 |
| Synonyms | GVS-111, Omberacetam (INN), N-phenylacetyl-L-prolylglycine ethyl ester, Noopept |
| Form / Variation | 30 MG Capsules (SKU C-028) |
Storage, Safety, and Handling
Storage Protocol
Store capsules at room temperature (15–25 °C) in sealed, moisture-proof packaging, away from direct light. Noopept is a stable small molecule; cold-chain shipping is not required for finished capsule formulations. Bulk lyophilized material should be stored at 2–8 °C with desiccant.
Handling & Compliance
Handle with standard precautions. The primary safety concern documented in the principal clinical trial was blood pressure elevation in 7/31 patients (22.6%); cardiovascular monitoring is appropriate. Sleep disturbances and irritability were each reported in fewer than 10% of patients. Overall adverse-event incidence was 1.8-fold lower than piracetam. Theoretical psychiatric risk (psychosis, mania) via AMPA glutamatergic overstimulation in susceptible individuals is biologically plausible and warrants screening; Noopept is unapproved in the United States and multiple Western jurisdictions. Source authentication and certificate of analysis verification are essential given widespread unregulated online distribution.
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