Metabolic modulators are classified as S4 substances according to the WADA banned substances list. WADA classes the drug as a metabolic modulator, just as it does insulin. On April 13, 2016, it was reported that WADA had issued updated guidelines allowing less than 1 microgram per milliliter of Mildronate for tests done before March 1, 2016.
The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl) propionate. It is a structural analog of γ-butyrobetaine, with an amino group replacing the C-4 methylene of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine. Since January 1, 2016, Mildronate has been on the World Anti-Doping Agency’s list of banned drugs. Although initial reports suggested meldonium is a non-competitive and non-hydroxylatable analogue of gamma-butyrobetaine; further studies have identified that Mildronate is a substrate for gamma-butyrobetaine dioxygenase. X-ray crystallographic and in vitro biochemical studies suggest that meldonium binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as an alternative substrate, and therefore a competitive inhibitor. These substances have the ability to modify how some hormones accelerate or slow down different enzymatic reactions in the body. In this way, these modulators can block the body’s conversion of testosterone into estrogen, which is necessary for females. Based on the overall effects these drugs have, they have been banned since 2001 from men’s competitions and 2005 for women’s. Normally, this enzyme’s action on its substrates γ-butyrobetaine and 2-oxoglutarate gives, in the presence of the further substrate oxygen, the products L-carnitine, succinate, and carbon dioxide; in the presence of this alternate substrate, the reaction yields malonic acid semialdehyde, formaldehyde (akin to the action of histone demethylases), dimethylamine, and (1-methylimidazolidin-4-yl)acetic acid, “an unexpected product with an additional carbon-carbon bond resulting from N-demethylation coupled to oxidative rearrangement, likely via an unusual radical mechanism.” The unusual mechanism is thought likely to involve Steven’s type rearrangement. The agency cited that “preliminary tests showed that it could take weeks or months for the drug to leave the body”. Mildronate is widely used by athletes to increase athletic performance and endurance.
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