Coluracetam, ≥99%

Chemical Information:

Technical Information:

Modes of action:

Coluracetam (BCI-540, MKC-231) is a synthetic Nootropic drug in the racetam family that was initially developed by Mitsubishi Tanabe Pharma Corporation and later by Brain Cells Inc. [1]

It was initially developed as a potential clinical therapy for Alzheimer’s Disease, but after trials failed to reach endpoints it was developed further for the treatment of major depressive disorder (MDD). Brain Cells Inc. reached phase 2a clinical trials which suggested that it may have potential as a medication for comorbid MDD and generalized anxiety disorder (GAD). [2]

Animal studies have shown post administration (10mg/kg) plasma concentrations of 4.289+/-0.641µg/mL (30 minutes), 0.717+/-0.350µg/mL (3 hours), and 0.037+/-0.010µg/mL (24 hours). After 14 days of use, there did not appear to be any effects on pharmacokinetics, indicating no tolerance build-up. [3]

Like other racetam compounds, Coluracetam has AMPA potentiating activity. Unlike most other racetams, it was additionally designed to activate the cholinergic system. [4] It is therefore of interest to researchers involved in studies regarding the choline transport system, protection against cognitive impairment, and neurochemical pathways for development of novel antidepressants. 

Coluracetam has cholinergic activity, significantly enhancing high-affinity choline uptake (HACU) – known to be the rate-limiting step of Acetylcholine (ACh) synthesis. BCl-540 increases Vmax (1.6fold) of HACU as well as Bmax (1.7fold) of [3H]-HC-3 binding, with strong affinity for high-affinity choline transporters (CHT1). [5]

The enhancement of HACU velocity is of great importance to researchers in the fields of Alzheimer’s and other dementias. A variety of research has pointed to perturbation in HACU activity in Alzheimer’s patients. [6] Preliminary evidence shows that the HACU activity-enhancing effects of BCl-540 may limited to subjects with malfunctioning acetylcholine systems, without significant effects on otherwise healthy subjects. [7]

In 1998, Akaike et al. published results indicating that Coluracetam has the potential to help protect the brain from glutamate neurotoxicity induced by ionomycin, through the suppression of NO synthesis triggered by increased Ca2+ influx. However, the study used a concentration higher than normal for the molecule (10µM), indicating that the results may not be practically relevant. [8]

Further scientific research

Please note that this is not a comprehensive account of the scientific research on Aniracetam to date. We have made a humble attempt to convey some of the most relevant research on the subject to date, in a variety of applications.

Clinical reviews:

There have not yet been any significant meta-analyses or clinical reviews published on the effects of Coluracetam.

Human studies:

There is room for further studies on the effects of Coluracetam in humans. Only one published clinical trial to-date.

After in-licensing BCl-540 from Mitsubishi Tanabe Pharma Corporation, Brain Cells Inc. began conducting research into the compound’s potential benefits for patients with major depressive disorder (MDD). The research culminated in a phase 2a clinical trial, published in 2010, examining the therapeutic potential for BCl-540 in patients showing comorbidity with MDD and generalized anxiety disorder (GAD).

The dosage used was 80mg, once to three times daily, for six weeks. Those patients dosed three times daily showed a 36% response rate, with a 12.2-point increase on HAM-D scores for those with comorbidity. Although this may seem like a low result, the authors state that current antidepressant treatments only have a 30-40% full response rate. [9]

Animal studies:

In 1994, Murai et al. published a study examining the memory-enhancing effects of MKC-231 in mice with decreased hippocampal acetylcholine. The study used behavioral tests including a delayed non-matching to sample task, using a T-maze. Mice were treated with AF64A to induce memory deficits and decreased hippocampal ACh content. Results showed that Coluracetam improved memory at a variety of doses (0.3, 1.0 and 3.0 mg/kg) for 11 days testing. In chronic experiments, the drug successfully reversed AF64A induced hippocampal ACh depletion, at doses of 0.3 and 1.0 mg/kg. [10]

In 2008, Takashina et al. produced a study examining the effects of Coluracetam on ACh synthesis and release in the hippocampus of normal and AF64A-treated rats. Treatment with MKC-231 (at dosages of 0.01 μm and 0.1 μm) produced a significant reversal of the effects of AF64A, both in HACU and ACh release. Additionally, Coluracetam showed an improvement in K+-induced ACh release in hippocampal slices with choline-containing artificial cerebro-spinal fluid (ACSF). [11]

Another study published in 2008, by Bessho et al., showed the potential use of BCl-540 in cognitive impairment studies. Oral treatment of 1 and 3mg/kg over 8 days produced significant learning improvements in rats treated with AF64A. Furthermore, cognitive improvements were seen for a full 24 hours post-administration of Coluracetam, even though the drug could no longer be detected at this time, indicating long-term benefits through interactions with choline transporter regulation system. [12]

References:

• [1] Drug Profile: Coluracetam. (2017). Adis Insight: Springer. Available online from https://adisinsight.springer.com/drugs/800001490. [Accessed July 5, 2017]
• [2] Coluracetam. Compound Summary for CID 214346. (2018). PubChem: Open Chemistry Database. U.S. National Library of Medicine, National Center for Biotechnology Information. Available online from https://pubchem.ncbi.nlm.nih.gov/compound/Coluracetam. [Accessed July 5, 2018]
• [3] Coluracetam. (2018) Examine.com. Available online from https://examine.com/supplements/coluracetam/. [Accessed July 5, 2018]. 
• [4] Lillrank SM, Collins CE. (2007). Psychological Disorders: Alzheimer's Disease and Other Dementias. Infobase Publishing. Dementia - 118 pages, pages 95-96
• [5] Takashina K. (2008). MKC-231, a choline uptake enhancer: (3) Mode of action of MKC-231 in the enhancement of high-affinity choline uptake, J Neural Transm (Vienna), 115(7):1037-46. 
• [6] Rodríguez-Puertas R, Pazos A, Zarranz JJ, Pascual J. (1994). Selective cortical decrease of high-affinity choline uptake carrier in Alzheimer's disease: an autoradiographic study using 3H-hemicholinium-3. J Neural Transm Park Dis Dement Sect, 8(3):161-9.
• [7] Bessho T, Takashina K, Tabata R, Ohshima C, Chaki H, Yamabe H, Egawa M, Tobe A, Saito K. (1996). Effect of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-1-yl)-N-(3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b] quinolin-4-yl)acetoamide on deficits of water maze learning in rats. Arzneimittelforschung, 46(4):369-73.
• [8] Akaike A. (1998). Protective effect of MKC-231, a novel high affinity choline uptake enhancer, on glutamate cytotoxicity in cultured cortical neurons. Jpn J Pharmacol, 76(2):219-22.
• [9] BrainCells Inc. Announces Results from Exploratory Phase 2a Trial of BCI-540 in Depression With Anxiety. (2010). Press Release. BrainCells.University of British Columbia, Trial Results, Phase II, Central Nervous System. 
• [10] Murai S, Saito H, Abe E, Masuda Y, Odashima J, Itoh T. (1994). MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice. J Neural Transm Gen Sect. 98(1):1-13.
• [11] Takashina K, Bessho T, Mori R, Eguchi J, Saito K. (2008). MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats. J Neural Transm (Vienna), 115(7):1027-35.
• [12] Bessho T, Takashina K, Eguchi J, Komatsu T, Saito K. (2008). MKC-231, a choline-uptake enhancer: (1) long-lasting cognitive improvement after repeated administration in AF64A-treated rats. J Neural Transm (Vienna), 115(7):1019-25.