Fasoracetam, ≥99%

Chemical Information:

Technical Information:

Background:

Fasoracetam (NFC-1, NS-105) was developed in the late 1980s for treating dementia-related cognitive impairment. It reached phase 3 clinical trials, but further research was then abandoned due to a lack of efficacy in patients with dementia. However, new research points to its potential antidepressant activity as well as the potential for use in targeted therapy for attention deficit hyperactivity disorder (ADHD). The compound has has marked activity on all three groups of metabotropic glutamate receptors (mGluRs), as well as a regulating effect on GABA-B receptor-mediated responses.[1]

Further information about the first trials conducted on Fasoracetam by the Japanese company, Nippon Shinyaku, Ltd., show that over $200 million was spent on its development before research was abandoned. In all trials, which were conduced on over one thousand patients with vascular dementia, the drug showed an excellent safety profile and no potential for addiction.[2] Current research tends to focus on the potential for use in attention deficit hyperactivity disorder (ADHD), and clinical trials are being conducted for this purpose.

In terms of comparison to other racetam compounds, this compound is much newer than most, having only been developed in the late 1980s. It also made it a lot further than many racetams in terms of its research and development (having got to phase III clinical trials for dementia).[3] In terms of its physiological effects, it is the one of the only racetam compounds to act on mGluRs, offering potentially unique benefits in a research setting. It is also the one of the only racetams to regulate GABA signaling, acting as an antagonist in acute administration, but upregulating signals when administered over time.

Modes of Action:

There are several key mechanisms of action for this novel research compound. In the mid-1990s, researchers found that Fasoracetam reverses the inhibition of cyclic AMP formation produced by the GABA-B agonist, Baclofen. Cyclic AMP is an important secondary messenger, and this research pointed towards possible Nootropic effects of Fasoracetam. 

In later experiments, the same researchers found that repeated administration of the compound increased the number of GABA-B receptors in the rat cerebral cortex, without affecting the binding properties of beta-adrenoceptors and 5-HT2 receptors. Their findings indicated the potential for antidepressant effects, possibly through the regulation of GABA-B receptor-mediated response.[4] Interestingly, studies point to GABA antagonism at acute dosages[3], while chronic administration tends to upregulate GABA signaling.[5] 

In one study, the cognitive performance-enhancing effects of Fasoracetam were compared to those of Aniracetam, Bifemelane, Idebenone, and Indeloxine. Fasoracetam showed antiamnesiac activity in a variety of animal models of cholinergic dysfunction. Results showed an increase of acetylcholine release from the cerebral cortex and high-affinity choline uptake (HACU), both in the cortex and hippocampus, in response to administration of the drug. NS-105 also inhibited the memory disruption produced by Baclofen. These results point to memory-enhancing effects through activity in the cholinergic system.[5]

Several studies have indicated the involvement of metabotropic glutamate (mGlu) receptors in the actions of Fasoracetam. In rat cerebrocortical membranes, the inhibitory action of Fasoracetam on forskolin-stimulated cAMP formation was blocked by a number of mGlu receptor agonists. Furthermore, in cerebral cortex cell cultures, the drug’s inhibitory action on adenylyl cyclase activity was shown to disappear after treatment with antisense oligodeoxynucleotides for several mGlu receptors.[6] These experiments were repeated in later studies with similar findings, indicating that the compound stimulates mGlu receptors subclasses that are coupled to adenylate cyclase, while acting as an antagonist to subclasses that are linked to phosphoinositides hydrolysis.[7]

Further Scientific Research

Although Fasoracetam has been studied in phase 3 clinical trials, there is still a relative lack of data published on it. The following information gives the reader some idea of the types of findings that have been published on this compound to date.

Clinical reviews:

In a review dated from 2016, researchers examined studies on the pharmacotherapy of the latest compounds in relation to ADHD.³ The researchers identified NFC-1 as a possible compound for targeted therapy for ADHD in patients who are ‘biomarker positive’ for mGluR/GTM gene network. Although the drug was abandoned in trials for the treatment of dementia, the authors proposed the potential for ADHD therapy and had a series of application for clinical trials approved by the FDA, beginning in 2015.[8]

Human Studies:

The latest study published is dated January 2018, and involved 30 adolescent participants, between the ages of 12-17 years, all with ADHD and associated mutations in mGluR network genes. In the study, pharmacokinetic profiling was done using dosages of 50-800 mg, and placebo-controlled study was completed over the following 4 weeks, using a dose advancement up to 400 mg. Results showed significant improvements in symptoms, with Clinical Global Impressions-Improvement (CSG-I) and Severity (CSG-S) scores recorded. Average CSG-I score at baseline was 3.79, with a score of 2.33 at week 5; while CSG-S average score was 4.83 at baseline and 3.86 at week 5. Further significant results were indicated for participants with mGluR Tier 1 variants. No differences in the incidence of adverse effects between placebo and active groups was recorded.[9]

In 1999, a study was published examining the pharmacokinetics of Fasoracetam. The aim of the study was to compare the pharmacokinetics of the compound in elderly subjects versus younger subjects. Fourteen healthy participants were included (7 ages 68-79 years, and 7 aged 20-32 years). Maximum plasma concentration (Cmax) was higher in the older subjects (3.06 +/- 0.69 vs. 2.13 +/- 0.34 micrograms/ml, the elderly vs. the young, mean +/- SD, p = 0.0117). Area under the plasma concentration curve (AUC) was also higher in the older subjects. Time to reach Cmax tended to be longer in older persons (2.1 +/- 1.1 vs. 1.3 +/- 0.5 hr, p = 0.1199) with a longer half-life. Total clearance of Fasoracetam was shown to take longer in the older group. This was thought to be due to decreased renal function in the elderly. The authors suggested that careful observation should be taken when prescribing the compound to elderly persons.[10]

Toxicity Reviews: 

There have not been any cases of toxic effects reported in studies on this compound to-date. Clinical trials show a low toxicity profile in both animals and humans.

Animal Studies:

In a study published in 1999, researchers examined the tissue distribution and transfer into the fetus and milk of Fasoracetam, in rats. Also researched were the effects on hepatic drug-metabolizing enzyme activity of repeated oral administration. Cmax tended to be reached at around 30 minutes after administration. The highest concentrations were found in the kidney and stomach, and lowest in white adipose tissue. No detection was found in the plasma 24 hours after administration.

No sex- nor pregnancy-related differences in distribution were found amongst the rats. In pregnant rats, the maximum concentration in the fetus was up to 66% of that in the maternal plasma, showing a high ability to transfer from mother to fetus. Milk concentrations were similar. Plasma concentrations did not change with the number of administrations, showing little to no development of tolerance. Repeated administration (at  a dosage of 10 mg/kg)  did not affect hepatic drug-metabolizing enzyme activities.[11]

The absorption, metabolism, and excretion of Fasoracetam was studied in rats, dogs, and monkeys, along with the protein-binding affinity both in vitro and in vivo. Data showed that Fasoracetam was almost completely absorbed in the small intestine, with very limited first-pass metabolism. In all animals, maximum plasma concentration was reached within one hour of after oral administration. Half-lives for rats, dogs, and monkeys were 0.67, 2.1, and 1.3 hours, respectively.

No significant sex-related pharmacokinetic differences were found for Fasoracetam, in all species. It was found that food affected absorption. Urinal metabolites included LAM-162 (oxidative metabolite with C-N cleavage of the piperidine ring), LAM-79 (metabolite with 4-hydroxylated piperidine ring), LAM-163 (metabolite with 3-hydroxylated piperidine ring) and M1 (not identified). The percentage Fasoracetam bound to serum proteins was less than 3.3% for all species tested, including humans. [12]

References:

• [1] Connolly J, Glessner J, Elia J, Hakonarson H. (2015). ADHD & Pharmacotherapy: Past, Present and Future: A Review of the Changing Landscape of Drug Therapy for Attention Deficit Hyperactivity Disorder. Therapeutic innovation & regulatory science, 49(5):632-642.
• [2] Moskowitz DH. Chpt 16: NeuroFix Contract with Nippon. Finding the Genetic Cause and Therapy for Adhd, Autism and 22q: A Journey Into Precision Medicine That Could Affect Millions Worldwide. BookBaby, 30 Jan 2017 - Medical - 264 pages.
• [3] Fasoracetam - Aevi Genomic Medicine. (n.d.). Adis Inisght Drug Profile. Available online from https://adisinsight.springer.com/drugs/800003134 [Accessed May 22, 2018]
• [4] Shimidzu T, Itoh Y, Oka M, Ishima T, Ukai Y, Yoshikuni Y, Kimura K. (1997). Effect of a novel cognition enhancer NS-105 on learned helplessness in rats: possible involvement of GABA(B) receptor up-regulation after repeated treatment. Eur J Pharmacol, 338(3):225-32.
• [5] Ogasawara T, Itoh Y, Tamura M, Mushiroi T, Ukai Y, Kise M, Kimura K. (1999). Involvement of cholinergic and GABAergic systems in the reversal of memory disruption by NS-105, a cognition enhancer. Pharmacol Biochem Behav, Sep;64(1):41-52.
• [6] Hirouchi M, Oka M, Itoh Y, Ukai Y, Kimura K. (2000). Role of metabotropic glutamate receptor subclasses in modulation of adenylyl cyclase activity by a nootropic NS-105. Eur J Pharmacol, 3;387(1):9-17.
• [7] Oka M, Itoh Y, Tatsumi S, Ma FH, Ukai Y, Yoshikuni Y, Kimura K. (1997). A novel cognition enhancer NS-105 modulates adenylate cyclase activity through metabotropic glutamate receptors in primary neuronal culture. Naunyn Schmiedebergs Arch Pharmacol, 356(2):189-96.
• [8] Safety and Efficacy Study of NFC-1 in Subjects Aged 12-17 Years With 22q11.2DS & Associated Neuropsychiatric Conditions. (2017) ClinicalTrials.gov Identifier: NCT02895906. Available online from https://clinicaltrials.gov/ct2/show/NCT02895906 
  
  [9] Elia J et al. (2018). Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling. Nat Commun, 9(1):4.
• [10] Kumagai Y, Yokota S, Isawa S, Murasaki M, Mukai H, Miyatake S. (1999). Comparison of pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly and young subjects. Int J Clin Pharmacol Res, 19(1):1-8.
• [11] Mukai H, Sugimoto T, Ago M, Morino A, Takaichi M, Ogawa Y, Seki H, Matsuura C, Esumi Y. (1999). Pharmacokinetics of NS-105, a novel cognition enhancer. 2nd communication: distribution and transfer into fetus and milk after single administration, and effects of repeated administration on pharmacokinetics and hepatic drug-metabolizing enzyme activities in rats. Arzneimittelforschung, 49(12):977-85.
• [12] Mukai H, Sugimoto T, Ago M, Morino A. (1999). Pharmacokinetics of NS-105, a novel cognition enhancer. 1st communication: absorption, metabolism and excretion in rats, dogs and monkeys after single administration of 14C-NS-105. Arzneimittelforschung, 49(11):881-90.