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Stereochemistry: Why Nootropics Work

A portrait of Heisenberg, looking pissed as usual.

Heisenberg certainly loves organic chemistry.

Chemistry is an ever-evolving science and it has certainly come a long way since we first started mixing chemicals in a futile attempt to turn lead into gold.

In modern times we have incredibly advanced techniques for synthesizing and isolating compounds, but massive discoveries are being made every day.

Chemical shapes in 3-D

The most relevant subset of chemistry for anyone interested in medications or nootropic supplements is undoubtedly organic chemistry – the study and use of all carbon-based compounds. In this vein, the importance one of the key aspects of organic chemistry, stereochemistry, was almost completely unknown to us until the last century.

Stereochemistry has nothing to do with noise and sound. Rather, it refers to the spatial arrangement of atoms that forms the structure of a molecule. A compound can have various isomers for example. These are compounds that have the same molecular formula, but have their atoms in a different position i.e. in a different order in the molecule.

The terms Cis and Trans refer to whether the molecules are on the same side of the double bond, denoted by the parallel lines, or across (trans) it. The molecules shown here would have the same molecular formula but a different structure, and as such different properties:

Cis and trans enantiomers of a molecule.

Shifting parts of a molecule around can change its function, and that’s not hard to grasp, but the delicate nature of compounds becomes evident when you look at a subset of isomers: enantiomers. Unless you’ve studied college level chemistry (or you’re a huge fan of Breaking Bad, like myself), you probably have never seen that word before.

Even as I write this, Microsoft Word is trying to tell me that I’ve spelled it wrong, even though I know I haven’t. Don’t worry, the concept sounds complicated, but it’s not so bad once you wrap your head around it.

Miniature molecular mirrors

Enantiomers are two versions of the same molecule that are non-super-imposable mirror images. This concept is a little hard to visualize, but is hopefully explained well in this picture:

Molecules mirror each other in a mixture.

If you’re having trouble imagining it, look up some more pictures online and see if that helps!

As you can see, if you were to hold the molecule up to a mirror you would get a reversed image of it. However, if you try and take that mirror image and “lift” it to put it on the original, the molecules that make it up don’t line up right. This is the case with any molecule that has four distinct groups attached to the central carbon.

So – why does this matter?

This might seem like a ridiculously tiny difference between the molecules, and it is, but that tiny difference can make the compound do completely different things. A relevant and pertinent example of when enantiomers come into play is the infamous thalidomide incident in the 1950s and 1960s.

Thalidomide was initially developed as an antiemetic (prevents nausea and vomiting) to be prescribed to pregnant women in order to counteract the effects of morning sickness. It was prescribed to women around the world for over a decade, but it then came out that over 10,000 children of mothers who had taken the drug were born with severe birth defects and deformities. This makes it a teratogenic substance i.e. one that can cause deformities.

This is due to several factors, incuding its ability to inhabit VEFG (vascular endothelial growth factor), a hormone key in angiogenesis (the growth of new blood vessels). It also inactivates cerebelon, an important protein that is needed for the growth and development of fetal limbs in the womb.

What’s interesting is that only the S enantiomer of thalidomide is teratogenic. The R enantiomer is a perfectly useful sedative and antiemetic drug! Unfortunately, this was not known to the chemists developing it at the time and as such all released versions of the drug contained a racemic mixture – one that contains approximately equal amounts of both the right handed and left handed variants. It is possible to completely isolate one version of the compound by running it through a molecular sieve or by converting them to diastereoisomers – which are not enantiomers.

Stereochemistry and nootropics

This is an extremely key part of the synthesis of all drugs and supplements, and nootropics are no exception, but a specific example would be the popular supplement Beta Alanine. It’s a favorite supplement for body builders and athletes as alanine is a precursor for carsonine, which is a key compound found in extremely high concentrations in the muscles and the brain.

As such, Beta Alanine is said to increase mental focus and decrease fatigue in people who regularly undertake high levels of physical stress or strenuous exercise. The beta variant of the compound is used, as opposed to the alpha variant, as it does not have a stereocenter – a part of the molecule that makes it chiral.

This would mean that both variants of the molecule would be present and could have unintended effects if ingested. As such, they would have to be removed to ensure consistency of the supplement, which would add an extra step to the production of the substance and make it significantly more expensive.

Conclusion: nootropic structure makes us smarter

All in all, stereochemistry is an extremely specific and small part of organic chemistry, but the net effect it has on how a molecule interacts with the body is almost unmatched.

Now that you know all about enantiomers and the thalidomide incident, you can appreciate the hard work and extremely advanced research that goes into creating all of these chemical substances and making them safe to consume for the general public.

Remember, it wasn’t that long ago that we sold a drug for morning sickness only to find out it resulted in extreme birth defects, so count yourself lucky that you live in such an advanced age of science.

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Click Here to Leave a Comment Below 2 comments
Reality - March 12, 2015

Err, nice article, but what on earth does it have to do with nootropics? You’re saying that noot researchers intentionally explore non-chiral compounds so that they don’t have to worry about separation? …don’t think so…

Off the top of my head I can immediately think of two chiral noots – phenylpiracetam (which is sold as a racemic mixture), and modafinil / armodafinil (the former being the racemic mixture, the latter being separated R- enantiomer).

Don’t get me wrong, I like stereochemistry and all! It’s just that…it’s got nothing to do with nootropics :/

Reply
Danny - March 13, 2015

Hey Reality, good question – though I think you’ve answered it yourself! R-modafinil has a stronger effect than does the racemic mixture. Perhaps the article should have mentioned that stereochemistry affects the function of only a select few nootropics. 🙂

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