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Coluracetam
Coluracetam
Coluracetam
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Coluracetam
Clinical data
ATC code
  • None
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: Not FDA approved
Identifiers
  • N-(2,3-Dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxo-1-pyrrolidinyl)acetamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H23N3O3
Molar mass341.411 g·mol−1
3D model (JSmol)
  • Cc1c(oc2c1c(c3c(n2)CCCC3)NC(=O)CN4CCCC4=O)C
  • InChI=1S/C19H23N3O3/c1-11-12(2)25-19-17(11)18(13-6-3-4-7-14(13)20-19)21-15(23)10-22-9-5-8-16(22)24/h3-10H2,1-2H3,(H,20,21,23)
  • Key:PSPGQHXMUKWNDI-UHFFFAOYSA-N

Coluracetam (INN; development code BCI-540; formerly MKC-231) is a purported nootropic agent of the racetam family.[1] It contains a chemical group that is a bioisostere of the 9-amino-tetrahydroacridine family. It was initially developed and tested by the Mitsubishi Tanabe Pharma Corporation for Alzheimer's disease. After the drug failed to reach endpoints in its clinical trials it was in-licensed by BrainCells Inc for investigations into major depressive disorder (MDD), which was preceded by being awarded a "Qualifying Therapeutic Discovery Program Grant" by the state of California.[2] Findings from phase IIa clinical trials have suggested that it would be a potential medication for comorbid MDD with generalized anxiety disorder (GAD).[3] BrainCells Inc is currently[when?] out-licensing the drug for this purpose.[4] It may also have potential use in prevention and treatment of ischemic retinopathy and retinal and optic nerve injury.[medical citation needed]

Coluracetam has been shown to reverse the loss of choline acetyltransferase production in the medial septal nucleus of rats exposed to phencyclidine (PCP), and is considered a potential therapeutic drug for schizophrenia.[5]

Mechanism of action

[edit]

Coluracetam enhances high-affinity choline uptake (HACU),[6] which is the rate-limiting step of acetylcholine (ACh) synthesis. Studies have shown coluracetam to improve learning impairment on a single oral dose given to rats which have been exposed to cholinergic neurotoxins. Subsequent studies have shown that it may induce long-lasting procognitive effects in cholinergic neurotoxin-treated rats by changing the choline transporter regulation system.[7]

Legality

[edit]

Australia

[edit]

Coluracetam is a schedule 4 substance in Australia under the Poisons Standard (February 2020).[8] A schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."[8]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Coluracetam

View on Grokipedia
from Grokipedia
Coluracetam (also known as MKC-231 or BCI-540) is a synthetic compound belonging to the family of drugs, characterized by its ability to enhance high-affinity choline uptake (HACU) in neural tissues, thereby promoting (ACh) synthesis and release in the . This mechanism targets signaling pathways, which are implicated in , learning, and cognitive function, and has been demonstrated in preclinical models of deficits, such as those induced by ethylcholine aziridinium ion (AF64A) in , where chronic oral administration (0.3–3.0 mg/kg) reversed hippocampal ACh depletion and improved performance in tasks like the T-maze delayed non-matching to sample. Originally developed by Mitsubishi Tanabe Pharma Corporation in the as a potential therapeutic for and cognitive decline. Coluracetam exhibits oral and long-lasting effects on in , with improvements observed up to 24 hours post-administration despite undetectable concentrations by that time. Further pharmacological investigations have explored coluracetam's modulation of the high-affinity choline transporter (CHT1/SLC5A7), though results vary; while early studies reported enhanced HACU in AF64A-treated hippocampal synaptosomes, subsequent assays in cell lines like HEK293 and failed to replicate direct modulation of transporter activity or surface localization under basal conditions. In addition to its effects, coluracetam has been associated with agonism, potentially contributing to its antidepressant-like properties by influencing . Preclinical data also suggest benefits in models of deficits, including and cognitive enhancement. Coluracetam advanced to clinical development when licensed by Mitsubishi Tanabe Pharma to BrainCells Inc. in 2005 for (MDD) and anxiety disorders, particularly comorbid MDD with (GAD). A phase IIa trial completed in 2010 evaluated its safety and efficacy in patients with MDD and anxiety, yielding preliminary positive signals for mood improvement, but the license was terminated in 2012, and development was discontinued across all indications by 2015. As of 2025, coluracetam remains an experimental agent without regulatory approval for any medical use, though it is available as a or in some markets for cognitive enhancement purposes.

Chemistry

Structure and properties

Coluracetam is a synthetic compound classified within the family, sharing structural similarities with through its inclusion of a 2-oxo-1-pyrrolidinyl moiety. It incorporates a bioisostere of the 9-amino-tetrahydroacridine group fused to a tetrahydrofuroquinoline core, distinguishing it from simpler racetams. The systematic chemical name of coluracetam is N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxo-1-pyrrolidinyl)acetamide. Its molecular formula is \ceC19H23N3O3\ce{C19H23N3O3}, and the molecular weight is 341.41 g/mol. Coluracetam presents as a white to off-white crystalline powder and is lipophilic in nature. It demonstrates in organic solvents including (2 mg/mL), (2 mg/mL), and (1 mg/mL), but is insoluble in at 7.2.

Synthesis

Coluracetam was initially synthesized in 1993 by Mitsubishi Tanabe Pharma in . The laboratory preparation of this analog generally starts with 2-hydroxyphenethylamine as the base material. Functional groups on this starting compound are protected to prevent unwanted side reactions during subsequent transformations. Key steps in the synthesis include of the hydroxyl and groups, followed by cyclization to construct the characteristic tetrahydrofuro[2,3-b] ring system. This cyclization typically employs condensation reactions with suitable carbonyl compounds or equivalents to form the fused heterocyclic core. The pyrrolidinyl is then attached to the core structure through an amidation reaction, often involving the corresponding acid chloride or activated ester of 2-(2-oxopyrrolidin-1-yl)acetic acid. Reduction steps may be incorporated to adjust saturation levels or remove protecting groups as needed. The overall route relies on a series of and reduction reactions, culminating in purification techniques such as recrystallization or to yield coluracetam in high purity suitable for applications.

Pharmacology

Mechanism of action

Coluracetam primarily enhances high-affinity choline uptake (HACU) in neuronal cells, serving as the rate-limiting step in acetylcholine synthesis and thereby increasing the availability of choline for production. This mechanism targets the sodium-coupled choline transporter (CHT1), promoting greater choline transport into presynaptic terminals of cholinergic neurons. Choline functions as the essential precursor for , a key involved in cognitive processes such as learning and . The compound demonstrates selective action on HACU sites, with preclinical studies in hippocampal synaptosomes from AF64A-treated rats showing a 1.6-fold increase in the maximum (Vmax) of choline uptake and a 1.7-fold increase in the maximum binding (Bmax) of the choline analog [³H]-hemicholinium-3. Early studies suggested these effects occur through direct interaction with CHT1, facilitating increased transporter density at synaptic membranes without altering substrate affinity (Km), though subsequent research in cell lines under basal conditions failed to replicate direct modulation of transporter activity or surface localization. experiments with concentrations ranging from 10⁻¹⁰ to 10⁻⁶ M further confirm significant HACU enhancement in rat hippocampal synaptosomes. Coluracetam may also modulate activity, potentially contributing to enhanced by influencing glutamate-mediated synaptic transmission. This interaction is suggested by data indicating neurogenic effects via pathways in preclinical models. Through its support of the pathway, coluracetam provides neuroprotective effects in rat models exposed to the AF64A, which induces hypofunction akin to Alzheimer's disease pathology. In these intracerebroventricular AF64A-treated rats (3 nmol/brain), coluracetam administration reverses deficits in levels and synaptic function, preserving neuronal integrity against toxin-induced damage.

Pharmacokinetics

Coluracetam is administered orally, with typical dosing in human clinical trials ranging from 80 mg once daily to 80 mg three times daily for the treatment of with concomitant anxiety. Pharmacokinetic data for coluracetam remain limited, primarily derived from , with sparse information available from early clinical development. In rats, oral doses of 0.3–3 mg/kg administered once daily for 11 days improved memory deficits without reported accumulation, suggesting steady-state achievement over repeated dosing. Limited preclinical data indicate rapid clearance. Despite rapid clearance, preclinical studies report cognitive benefits persisting up to 24 hours, suggesting sustained downstream effects on signaling.

Medical uses

Cognitive enhancement

Preclinical studies have demonstrated that coluracetam (also known as MKC-231) improves learning impairments in animal models of dysfunction. In rats treated with the neurotoxin AF64A, which induces deficits mimicking aspects of pathology, repeated oral administration of coluracetam at doses of 1–3 mg/kg over 8 days significantly enhanced performance in the water maze task, with cognitive benefits persisting up to 24 hours after the final dose despite undetectable levels in the brain. This improvement is attributed to coluracetam's enhancement of high-affinity choline uptake (HACU), leading to sustained increases in activity in the hippocampus. Coluracetam has also been shown to support memory formation processes in the hippocampus, a key region for learning. By promoting HACU, it bolsters , which is essential for and . Animal models suggest potential benefits for age-related cognitive decline and , as coluracetam's reversal of AF64A-induced deficits addresses hypofunction central to these conditions. Anecdotal reports from users, including a documented case study of a healthy adult taking 20 mg daily for three months, describe subjective improvements in focus, sensory perception—such as enhanced visual clarity and vividness—and abstract reasoning. In this case, the participant reported "HD-like" visual enhancements by the second month, alongside easier connection of ideas and faster analytical processing, though objective pre-post testing showed modest gains without statistical significance. These effects align with coluracetam's cholinergic enhancement, providing a brief mechanistic basis for observed cognitive benefits.

Mood disorders

Coluracetam has been investigated as a potential treatment for (MDD) with comorbid (GAD), particularly in patients who exhibit symptoms unresponsive to standard selective serotonin reuptake inhibitors (SSRIs). This targeting stems from its role as a high-affinity choline uptake enhancer, which increases synthesis and modulates signaling in regions implicated in mood regulation, such as the hippocampus and . hyperactivity has been linked to —a core feature of MDD characterized by diminished pleasure and motivation—and associated anxiety, where enhanced tone may exacerbate these symptoms in SSRI non-responders by disrupting reward processing and emotional reactivity. Preliminary evidence from a phase IIa conducted by Brain Cells Inc., involving patients with comorbid MDD and GAD, demonstrated positive signals of efficacy, including improvements in depressive symptoms. These findings suggest coluracetam may offer benefits in alleviating residual anhedonic and anxiogenic symptoms, potentially through its augmentation of without the broad serotonergic effects of traditional antidepressants. However, the trial results remain unpublished in peer-reviewed literature, limiting broader validation, and further controlled studies are needed to confirm these observations. Development was discontinued in 2015, and coluracetam is not approved for any medical use. Preclinical studies have suggested potential benefits for addressing negative symptoms of , such as social withdrawal and blunted affect, via enhancement that may indirectly potentiate receptors and signaling. modulation has shown promise in preclinical models for improving cognitive and motivational deficits in , but data specific to coluracetam are limited to early investigations, with no clinical trials reported. Neuroprotective effects of coluracetam, including stabilization of pathways, may contribute to mood regulation in these contexts by mitigating neuronal vulnerability to stress-induced damage.

Adverse effects

Short-term effects

Coluracetam is generally well tolerated in limited clinical evaluations, with short-term adverse effects reported infrequently. In the phase II trial conducted by BrainCells Inc. (NCT00621270) with an estimated enrollment of 115 participants receiving up to 240 mg daily (80 mg three times daily) for six weeks, safety was evaluated but no detailed results, including on adverse events, have been publicly reported. Anecdotal user reports commonly describe increased anxiety, mental fog, and difficulty concentrating as short-term effects, particularly in individuals sensitive to modulation. These symptoms may relate briefly to potential overstimulation from enhanced high-affinity choline uptake. Mild gastrointestinal disturbances, such as or upset, have been noted at higher doses based on user experiences. Neurological effects including headaches and sensations of overstimulation occur occasionally in sensitive users, often attributed to choline depletion during acetylcholine synthesis.

Long-term safety

Coluracetam exhibits low potential, with no evidence of dependence or withdrawal symptoms reported in available preclinical or clinical data on racetams, including this compound. Preclinical toxicity studies on racetams, the class to which coluracetam belongs, indicate a generally favorable profile, though specific data for coluracetam are limited; animal investigations have identified potential risks of reproductive, testicular, gastrointestinal, and renal toxicity with chronic exposure to certain analogs like and . The aforementioned phase II evaluated safety at doses up to 240 mg daily for six weeks but provided no publicly available detailed findings and does not address long-term use. Long-term safety remains largely unstudied, with no dedicated chronic human trials available to assess , tolerance development, or potential imbalances from prolonged enhancement of high-affinity choline uptake. This gap parallels broader concerns in research, where sustained effects on brain health require further investigation, and no new clinical data have emerged as of 2025. Contraindications are not explicitly defined, but caution is advised in conditions like or due to theoretical risks of mood destabilization from modulation, though direct evidence is absent.

History

Development

Coluracetam, originally known by the developmental code MKC-231, originated in through research conducted by Mitsubishi Tanabe Pharma Corporation in the early . The compound was synthesized as part of efforts to address deficits associated with neurodegenerative conditions. Initial preclinical studies for MKC-231 were reported in , marking its characterization as a agent capable of enhancing high-affinity choline uptake in neuronal models. The primary goal of this development was to create a therapeutic for by potentiating , specifically through mechanisms that promote choline availability for synthesis. Mitsubishi Tanabe Pharma positioned MKC-231 as a selective choline uptake enhancer, distinguishing it from broader inhibitors then in use. Preclinical studies during this period focused on its potential to mitigate impairments induced by hypofunction, such as those modeled by AF64A treatment in . In 2006, the rights to MKC-231 (later redesignated BCI-540) were licensed from Pharma to BrainCells Inc., a U.S.-based firm specializing in disorders. This transfer occurred after Mitsubishi suspended further advancement due to insufficient in Alzheimer's-focused trials, despite favorable profiles. BrainCells acquired the compound to leverage its platform for neurogenic agents. By the late 2000s, development shifted toward investigating coluracetam's applications in mood disorders, including and anxiety, reflecting a strategic pivot from treatment to broader neuropsychiatric indications. This repurposing aligned with emerging evidence of the compound's effects on neural plasticity and neurotransmitter modulation beyond pathways.

Clinical research

Coluracetam, also known as MKC-231, has been evaluated in preclinical animal models for its potential to address memory impairments associated with dysfunction. In studies using the AF64A-treated rat model, which induces memory deficits through selective inhibition of high-affinity choline uptake, of coluracetam at doses of 0.3 to 3.0 mg/kg significantly improved learning and performance in the T-maze delayed non-matching to sample task, with effects observed after chronic administration for 11 days. These findings suggest coluracetam's role in enhancing neurotransmission, though specific reversal of scopolamine-induced deficits has not been directly demonstrated in available literature. Human on coluracetam remains limited, with the primary study being a Phase IIa trial conducted by BrainCells Inc. in 2009. This randomized, double-blind, placebo-controlled trial enrolled approximately 90 patients with (MDD), often comorbid with anxiety, who received 80 mg of coluracetam orally three times daily for 6 weeks as an adjunct to existing therapy. The trial demonstrated improvements in depressive symptoms, including reductions in self-reported depression severity, though detailed outcomes on standardized scales like the Hamilton Depression Rating Scale were not publicly disclosed in full. Safety data indicated good tolerability, with no serious adverse events reported. Following the Phase IIa results, no Phase III trials were initiated. The was terminated in May 2012, and the compound became available for relicensing in June 2012. BrainCells Inc. ceased operations in 2014, and development of coluracetam for MDD, anxiety, or was discontinued across all indications by 2015. The halt appears linked to strategic reprioritization rather than safety concerns, leaving coluracetam without further large-scale human evaluation. More recent evidence comes from individual case reports in the 2020s, highlighting potential cognitive effects. A 2023 mixed-methods of a healthy 36-year-old male administered 20 mg daily for 3 months, combined with lifestyle factors like exercise and adequate , reported enhancements in (score increase from 90 to 100), pattern recognition (30 to 38), and analytical thinking (88 to 100) on the Brain Metrics Initiative IQ test, alongside abstract reasoning gains (60 to 63), though spatial orientation slightly declined (55 to 50). Statistical analysis showed no significant pre-post differences overall (p = 0.75) but a strong relationship among cognitive variables (R² = 0.95, p = 0.004), suggesting possible benefits in non-clinical populations. These anecdotal findings warrant controlled studies for validation. As of November 2025, no further clinical advancement has occurred.

Australia

In Australia, coluracetam is classified as a Schedule 4 substance under the Poisons Standard, designating it as a prescription-only . It has no approved therapeutic uses and is not included in the Australian Register of Therapeutic Goods (ARTG), which prohibits its marketing, advertising, or sale without prior approval from the (TGA). Personal importation is allowed under the TGA's Personal Importation Scheme for or personal use, but only under strict conditions, including a maximum supply of three months' worth at the recommended dose and exclusion of goods intended for resale. The TGA enforces these regulations, ensuring no over-the-counter sales or unauthorized distribution occur. As an unapproved in global contexts, coluracetam's access in Australia remains highly restricted to protect .

United States

Coluracetam has not received approval from the for any therapeutic use in the , as it lacks a demonstrating safety and efficacy. As an unapproved drug, it cannot be legally prescribed by healthcare providers or marketed and sold as a under the Federal Food, Drug, and Cosmetic Act. This regulatory status positions coluracetam outside standard medical channels, prohibiting its distribution for human consumption. In practice, coluracetam is available in the U.S. as a , intended solely for laboratory and scientific experimentation, with vendors explicitly stating it is not for human or veterinary use to comply with FDA guidelines. Such sales typically occur through specialized online suppliers targeting researchers, but any promotion implying benefits for personal enhancement violates federal labeling and advertising rules. The (DEA) has not scheduled coluracetam under the , classifying it as an unscheduled substance with no federal restrictions on possession or distribution beyond general drug laws. However, despite its unscheduled status, coluracetam is frequently marketed online as a for cognitive enhancement, prompting FDA enforcement actions against vendors for unverified claims and misbranding of unapproved racetams since the 2010s.

Other countries

In the , coluracetam is classified as an unlicensed under the Human Medicines Regulations 2012, administered by the Medicines and Healthcare products Regulatory Agency (MHRA). While possession for personal use is not illegal, the sale, supply, or importation for commercial purposes of unlicensed medicines is prohibited, with personal importation restricted to limited quantities under specific exemptions for individual needs. In Canada, coluracetam is unscheduled and not approved by as a or natural health product, prohibiting its sale or distribution without regulatory authorization. Personal possession is legal, and importation for personal use is permitted up to a 90-day supply, provided it is not intended for resale and complies with customs declarations. The legal status of coluracetam in the varies by , as it lacks authorization from the for any medical indication. Generally, it is unregulated as a substance but not approved for therapeutic use; for instance, in , it is unscheduled under the Federal Institute for Drugs and Medical Devices (BfArM) and may only be handled as a without marketing claims. Coluracetam, known developmentally as MKC-231, was synthesized in by Mitsubishi Tanabe Pharma Corporation as a potential treatment for but has not received approval from the Ministry of Health, Labour and Welfare for commercial availability. It remains restricted to research purposes in , with no provisions for over-the-counter or prescription use.

References

  1. https://pubmed.ncbi.nlm.nih.gov/7710736/
  2. https://adisinsight.springer.com/drugs/800001490
  3. https://pubmed.ncbi.nlm.nih.gov/18461272/
  4. https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00040/full
  5. https://go.drugbank.com/drugs/DB21278
  6. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62446491.htm
  7. https://pubmed.ncbi.nlm.nih.gov/18461273/
  8. https://pubmed.ncbi.nlm.nih.gov/8740080/
  9. https://patents.google.com/patent/US20090088449A1/en
  10. https://pubmed.ncbi.nlm.nih.gov/18446264/
  11. https://clinicaltrials.gov/study/NCT00621270
  12. https://link.springer.com/article/10.1007/BF01277590
  13. https://clinmedjournals.org/articles/ijcb/international-journal-of-cognition-and-behaviour-ijcb-6-016.php?jid=ijcb
  14. https://wjpr.s3.ap-south-1.amazonaws.com/article_issue/1456748491.pdf
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC7192315/
  16. https://www.nature.com/articles/s41598-017-01088-6
  17. https://www.braintropic.com/nootropics/coluracetam/
  18. https://muscleandbrawn.com/nootropics/everything-to-know-about-coluracetam-2025/
  19. https://www.tga.gov.au/sites/default/files/publication-interim-decisions-amending-or-not-amending-current-poisons-standard-february-2019.pdf
  20. https://www.researchgate.net/publication/347037543_Effects_of_MKC-231_a_novel_choline_uptake_enhancer_on_AF64A-induced_reduction_of_high_affinity_choline_uptake_and_impairment_of_water_maze_learning_in_rats
  21. https://www.biospace.com/braincells-inc-in-licenses-clinical-stage-cns-compound-from-mitsubishi-pharma-corporation
  22. https://philoneuro.com/2014/12/16/coluracetams-pharmacological-mechanisms-a-perspective-piece/
  23. https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/personal-importation-scheme
  24. https://www.tga.gov.au/products/unapproved-therapeutic-goods
  25. https://www.gov.uk/government/news/medicines-watchdog-makes-record-seizure-of-experimental-smart-drugs
  26. https://www.researchgate.net/publication/5392310_MKC-231_a_choline-uptake_enhancer_1_Long-lasting_cognitive_improvement_after_repeated_administration_in_AF64A-treated_rats
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