Fasoracetam – Cognitive Enhancer Research Compound / Articles

Fasoracetam: Chemical and Pharmacological Aspects of a Research Nootropic

1. Introduction

Fasoracetam (INN) is an experimental drug of the racetam family that was never marketed. It is a putative nootropic compound that has been investigated for its cognitive-enhancing effects. Initially studied for vascular dementia, it failed to show sufficient efficacy in clinical trials for that indication. The drug was subsequently repurposed and is currently being investigated for neuropsychiatric and neurodevelopmental disorders, most notably Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in individuals with specific genetic variations in the glutamatergic system.

Fasoracetam is also known by several research codes: AEVI-001, AEVI-004, LAM-105, MDGN-001, NB-001, NFC-1, and NS-105. It is sometimes referred to as (5R)-5-oxo-D-prolinepiperidinamide.

2. Chemical Structure and Nomenclature

IUPAC name: (5R)-5-(piperidine-1-carbonyl)pyrrolidin-2-one

Molecular formula: C₁₀H₁₆N₂O₂

Molecular weight: 196.25 g/mol

CAS number: 110958-10-5

SMILES: C1CCN(CC1)C(=O)C2CCC(=O)N2

InChIKey: GOWRRBABHQUJMX-MRVPVSSYSA-N

Structural features: Fasoracetam belongs to the racetam family, which are derivatives of pyrrolidin-2-one (2-oxo-pyrrolidine). The core structure is a pyrrolidinone ring substituted at the 5-position with a piperidine-1-carbonyl group. The molecule has one defined stereocenter with an absolute (R)-configuration.

3. Physicochemical Properties

Fasoracetam typically appears as a white to off-white crystalline powder. It is soluble in polar organic solvents such as dimethyl sulfoxide (DMSO) and has moderate solubility in water, which is pH-dependent. The compound is relatively stable at room temperature under dry conditions, protected from light. It is sensitive to strong oxidizing agents and hydrolytic conditions.

4. Pharmacological Mechanism of Action

Fasoracetam's primary pharmacological effects can be categorized into three main areas: modulation of the glutamatergic system, upregulation of the GABAergic system, and enhancement of cholinergic activity.

Modulation of Metabotropic Glutamate Receptors (mGluRs)

The cornerstone of fasoracetam's mechanism is its function as a modulator of metabotropic glutamate receptors (mGluRs). Preclinical and clinical evidence suggests that a primary mechanism of action for fasoracetam is the modulation of these G-protein coupled receptors, which play a crucial role in modulating synaptic transmission and neuronal excitability. Fasoracetam appears to agonize all three groups of metabotropic glutamate receptors. In vitro studies on mouse neurons have shown that fasoracetam modulates mGluR II/III activity.

GABAergic System Modulation

Fasoracetam also modulates the gamma-aminobutyric acid (GABA) system, which is responsible for inhibitory neurotransmission in the brain. The exact mechanism may involve antagonism of γ-aminobutyric acid (GABA)B receptors, a mechanism not found in other nootropics such as aniracetam. Fasoracetam has the ability to upregulate GABA-B receptors, increasing GABA concentration in the central nervous system. In studies in rats, it blocked memory disruptions caused by baclofen (a GABAB agonist) and upregulated production of GABAB receptors after repeat dosing.

Cholinergic System Enhancement

Fasoracetam also interacts with neuronal acetylcholine (ACh) receptors. It is reported to improve learning and memory and to activate cholinergic neurotransmission. This unique mechanism of action, which involves the modulation of cholinergic, glutamatergic, and GABAergic systems, provides a strong rationale for its potential therapeutic applications.

5. Pharmacokinetics

Fasoracetam exhibits high bioavailability, ranging from 79% to 97% in animal studies. Its elimination half-life is approximately 4 to 6.5 hours.

In a pharmacokinetic study involving adolescents aged 12–17 years with ADHD, single-dose parameters were evaluated across doses from 50 mg to 800 mg. At a 50 mg dose, the median time to reach maximum concentration (T_max) was 1.5 hours, with a maximum concentration (C_max) of 1.19 µg/ml. For the 100 mg dose, T_max was 1.9 hours and C_max was 1.72 µg/ml. At 200 mg and 400 mg, T_max values were 1.3 hours for both. For the 800 mg dose, the area under the curve (AUC(0–∞)) was 6.87 h × µg/ml.

These data indicate that fasoracetam is rapidly absorbed and exhibits a dose-proportional pharmacokinetic profile within the studied range.

6. Clinical Research and Potential Applications

ADHD and Genetic Subtypes

Fasoracetam is currently being tested in Phase III/II clinical trials for the treatment of Attention Deficit Disorder With Hyperactivity in people with genetic disorders impacting mGlu receptors. A 2018 study published in Nature Communications reported on a 5‑week, open-label, single-blind, placebo-controlled study of 30 adolescents (age 12–17) with ADHD harboring mutations in mGluR network genes. Treatment with NFC-1 (fasoracetam) resulted in significant improvement as measured by Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores.

Importantly, individuals who harbored copy number variations (CNVs) within the glutamatergic gene network had a better therapeutic response. Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants. This suggests that fasoracetam may be particularly effective in ADHD patients with specific genetic variations in the glutamatergic system.

Other Potential Indications

Fasoracetam has also been investigated for other conditions, including:

Anxiety disorders
Autism spectrum disorders (ASD)
Alzheimer's disease (as a potential anti-Alzheimer pharmaceutical)
Tourette syndrome (treatment may be based on assessment of genetic alterations in mGluR network genes)
Depression (preclinical data suggest potential)

7. Safety and Adverse Effects

Clinical trial data: In the 5‑week study of adolescents with ADHD, no serious treatment-emergent adverse events (TEAEs) were reported, and the majority of TEAEs were mild‑to‑moderate in severity. These data indicate that NFC‑1 was generally well‑tolerated. There were no differences in the incidence of adverse events between placebo week and weeks on active drug.

Common side effects: In the small clinical studies that exist, side effects have generally been mild to moderate and may include headache, nausea/gastrointestinal discomfort, fatigue or sleep changes (either drowsiness or insomnia), dizziness, and irritability or mood changes.

Toxicity classifications: Some sources classify fasoracetam with R-phrases indicating: R28: Very toxic if swallowed; R38: Irritating to skin; R41: Risk of serious damage to eyes; R48: Toxic; danger of serious damage to health by prolonged exposure.

Regulatory status: Fasoracetam has not been approved by the FDA. In Australia, it is classified as S4 (Prescription only).

8. Research and Development Status

Fasoracetam is an experimental drug that was never marketed. It is currently being investigated in clinical studies. The drug is also being marketed in the form of capsules for research purposes aimed at investigation of cognition and memory disorders.

Clinical trials that have been conducted or are ongoing include:

NCT03609619: Efficacy and Safety of AEVI-001 in Children and Adolescents With ADHD
NCT03006367: Pharmacokinetic and Tolerability Study of NFC-1 in Subjects Aged 6–17 Years With ADHD
NCT02286817: Study of NFC-1 in Adolescents with ADHD and Glutamatergic Gene Network Variants

9. Conclusion

Fasoracetam is a research nootropic compound belonging to the racetam family with a unique mechanism of action that distinguishes it from other compounds in its class. Its primary effects involve modulation of metabotropic glutamate receptors (mGluRs), upregulation of GABA-B receptors, and enhancement of cholinergic neurotransmission. While initial research focused on vascular dementia and cognitive enhancement, the compound has been repurposed for investigation in ADHD, particularly in patients with specific genetic variations in the glutamatergic system.

Clinical studies have shown promising results in adolescents with ADHD harboring mGluR network gene mutations, with significant improvements in clinical ratings and good tolerability. However, fasoracetam has not received regulatory approval for any indication and remains an experimental compound. Ongoing research continues to explore its potential in ADHD, anxiety, autism spectrum disorders, and other neuropsychiatric conditions.

This article is for informational purposes only and does not constitute medical advice. The use of research compounds should only be conducted in accordance with applicable laws and regulations, and under appropriate oversight.