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Di-acetyl creatine ethyl ester is at least 1000 times more effective than regular creatine

Di-acetyl creatine ethyl ester is at least 1000 times more effective than regular creatine
Italian neurologists are experimenting with a new creatine analogue, di-acetyl creatine ethyl ester. According to their in vitro studies this analogue is no less than 1000 times more effective than regular creatine. It could be that di-acetylcreatine ethyl ester, when taken orally, is deactivated in the stomach. But maybe it's not, or maybe you can inject this stuff. And then... Well, this super creatine that will probably end up on the WADA doping list.

There are a few congenital neurological disorders where cells can not take up creatine. The creatine transporters of the cells don't work. Researchers try to remedy these disorders by designing creatine analogues that can enter cells without needing a creatine transporter.

Italian neurologists, affiliated with the University of Genova, report in Neuroscience Letters that they are conducting experiments with a new creatine analogue: di-acetylcreatine ethyl ester.

Di-acetyl creatine ethyl ester is at least 1000 times more effective than regular creatine

You can see the structural formula of di-acetyl creatine ethyl ester above. The ethyl group on the right and the two acetyl groups on the left make the molecule lipophilic. This means that the molecule should be able to pass throught cell membranes on its own. In the cell, enzymes will remove the ethyl and acetyl moieties - and create - drumroll please - creatine.

Study & results
In petri dishes the Italians exposed brain cells to creatine. On one occasion the brain cells floated in a liquid that mimics the brain's environment; on another occasion the researchers used the same liquid, but without chloride. The figure below shows that in the first experiment the concentration of creatine in the cells rose. In the second experiment it did not.

Di-acetyl creatine ethyl ester is at least 1000 times more effective than regular creatine

The creatine transporter, the protein through which cells can absorb creatine, needs chloride in its environment to function. Without it, the transporter doesn't work. This way you can simulate the effect of congenital abnormalities, in which the creatine transporter does not function properly due to an error in the genetic code.

In another experiment, the researchers exposed brain cells, in an environment without chloride, to di-acetylcreatine ethyl ester [DAC]. That compound increased the creatine concentration even more than creatine in an environment with chloride. And if you look at the concentration of di-acetylcreatine ethyl ester that the researchers used, and compare it with the concentration of creatine from above, then you understand why we find di-acetylcreatine ethyl ester to be an interesting substance...

Di-acetyl creatine ethyl ester is at least 1000 times more effective than regular creatine

"Interestingly, di-acetylcreatine-ethyl-ester exerts its positive effects at micromolar concentrations", the Italians write, "i.e. at a much lower concentration than all the other creatine derivatives we tested so far."

The analogues to which the researchers are referring to are creatine benzyl ester, creatine-magnesium complex acetate and phosphocreatine-magnesium complex acetate. [Neurochem Res. 2008 May;33(5):765-75.] [Neuroscience. 2006 Nov 3;142(4):991-7.]

"This likely occurs because of its marked lipophilicity, conferred by the two acetyl groups and by the ethyl group that are bound to the creatine skeleton. Effectiveness at such a low concentration is undoubtedly a potential advantage in a possible therapeutic use."

The researchers emphasize that they experimented with cells in a test tube, not with organisms.

"As a word of caution, we should however remember that in the model we used (in vitro brain slices) creatine or its derivatives (di-acetylcreatine-ethyl-ester in this case) need crossing one membrane only, i.e. the cell plasma membrane. In vivo, they need crossing several membranes [...]. We thus need in vivo experiments to verify if di-acetylcreatine-ethyl-ester will succeed in sequentially crossing all these different membranes."

The American research company Lumos Pharma []] sponsored the Italian research. Lumos Pharma is developing new drugs for neurological disorders that result from defective creatine transporters.

Neurosci Lett. 2018 Feb 5;665:217-23.

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